Prescription Drugs
OxyContin Abuse and Diversion and Efforts to Address the Problem
Gao ID: GAO-04-110 December 19, 2003
Amid heightened awareness that many patients with cancer and other chronic diseases suffer from undertreated pain, the Food and Drug Administration (FDA) approved Purdue Pharma's controlled-release pain reliever OxyContin in 1995. Sales grew rapidly, and by 2001 OxyContin had become the most prescribed brandname narcotic medication for treating moderate-to-severe pain. In early 2000, reports began to surface about abuse and diversion for illicit use of OxyContin, which contains the opioid oxycodone. GAO was asked to examine concerns about these issues. Specifically, GAO reviewed (1) how OxyContin was marketed and promoted, (2) what factors contributed to the abuse and diversion of OxyContin, and (3) what actions have been taken to address OxyContin abuse and diversion.
Purdue conducted an extensive campaign to market and promote OxyContin using an expanded sales force to encourage physicians, including primary care specialists, to prescribe OxyContin not only for cancer pain but also as an initial opioid treatment for moderate-to-severe noncancer pain. OxyContin prescriptions, particularly those for noncancer pain, grew rapidly, and by 2003 nearly half of all OxyContin prescribers were primary care physicians. The Drug Enforcement Administration (DEA) has expressed concern that Purdue's aggressive marketing of OxyContin focused on promoting the drug to treat a wide range of conditions to physicians who may not have been adequately trained in pain management. FDA has taken two actions against Purdue for OxyContin advertising violations. Further, Purdue did not submit an OxyContin promotional video for FDA review upon its initial use in 1998, as required by FDA regulations. Several factors may have contributed to the abuse and diversion of OxyContin. The active ingredient in OxyContin is twice as potent as morphine, which may have made it an attractive target for misuse. Further, the original label's safety warning advising patients not to crush the tablets because of the possible rapid release of a potentially toxic amount of oxycodone may have inadvertently alerted abusers to methods for abuse. Moreover, the significant increase in OxyContin's availability in the marketplace may have increased opportunities to obtain the drug illicitly in some states. Finally, the history of abuse and diversion of prescription drugs, including opioids, in some states may have predisposed certain areas to problems with OxyContin. However, GAO could not assess the relationship between the increased availability of OxyContin and locations of abuse and diversion because the data on abuse and diversion are not reliable, comprehensive, or timely. Federal and state agencies and Purdue have taken actions to address the abuse and diversion of OxyContin. FDA approved a stronger safety warning on OxyContin's label. In addition, FDA and Purdue collaborated on a risk management plan to help detect and prevent OxyContin abuse and diversion, an approach that was not used at the time OxyContin was approved. FDA plans to provide guidance to the pharmaceutical industry by September 2004 on risk management plans, which are an optional feature of new drug applications. DEA has established a national action plan to prevent abuse and diversion of OxyContin. State agencies have investigated reports of abuse and diversion. In addition to developing a risk management plan, Purdue has initiated several OxyContin-related educational programs, taken disciplinary action against sales representatives who improperly promoted OxyContin, and referred physicians suspected of improper prescribing practices to the authorities.
Recommendations
Our recommendations from this work are listed below with a Contact for more information. Status will change from "In process" to "Open," "Closed - implemented," or "Closed - not implemented" based on our follow up work.
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GAO-04-110, Prescription Drugs: OxyContin Abuse and Diversion and Efforts to Address the Problem
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Report to Congressional Requesters:
United States General Accounting Office:
GAO:
December 2003:
Prescription Drugs:
OxyContin Abuse and Diversion and Efforts to Address the Problem:
OxyContin Abuse and Diversion:
GAO-04-110:
GAO Highlights:
Highlights of GAO-04-110, a report to congressional requesters
Why GAO Did This Study:
Amid heightened awareness that many patients with cancer and other
chronic diseases suffer from undertreated pain, the Food and Drug
Administration (FDA) approved Purdue Pharma‘s controlled-release pain
reliever OxyContin in 1995. Sales grew rapidly, and by 2001 OxyContin
had become the most prescribed brand-name narcotic medication for
treating moderate-to-severe pain. In early 2000, reports began to
surface about abuse and diversion for illicit use of OxyContin, which
contains the opioid oxycodone.
GAO was asked to examine concerns about these issues. Specifically,
GAO reviewed (1) how OxyContin was marketed and promoted, (2) what
factors contributed to the abuse and diversion of OxyContin, and
(3) what actions have been taken to address OxyContin abuse and
diversion.
What GAO Found:
Purdue conducted an extensive campaign to market and promote OxyContin
using an expanded sales force to encourage physicians, including
primary care specialists, to prescribe OxyContin not only for cancer
pain but also as an initial opioid treatment for moderate-to-severe
noncancer pain. OxyContin prescriptions, particularly those for
noncancer pain, grew rapidly, and by 2003 nearly half of all OxyContin
prescribers were primary care physicians. The Drug Enforcement
Administration (DEA) has expressed concern that Purdue‘s aggressive
marketing of OxyContin focused on promoting the drug to treat a wide
range of conditions to physicians who may not have been adequately
trained in pain management. FDA has taken two actions against Purdue
for OxyContin advertising violations. Further, Purdue did not submit
an OxyContin promotional video for FDA review upon its initial use in
1998, as required by FDA regulations.
Several factors may have contributed to the abuse and diversion of
OxyContin. OxyContin‘s availability in doses that were twice as potent
as morphine may have made it an attractive target for misuse. Further,
the original label‘s safety warning advising patients not to crush the
tablets because of the possible rapid release of a potentially toxic
amount of oxycodone may have inadvertently alerted abusers to methods
for abuse. Moreover, the significant increase in OxyContin‘s
availability in the marketplace may have increased opportunities to
obtain the drug illicitly in some states. Finally, the history of
abuse and diversion of prescription drugs, including opioids, in some
states may have predisposed certain areas to problems with OxyContin.
However, GAO could not assess the relationship between the increased
availability of OxyContin and locations of abuse and diversion because
the data on abuse and diversion are not reliable, comprehensive, or
timely.
Federal and state agencies and Purdue have taken actions to address
the abuse and diversion of OxyContin. FDA approved a stronger safety
warning on OxyContin‘s label. In addition, FDA and Purdue collaborated
on a risk management plan to help detect and prevent OxyContin abuse
and diversion, an approach that was not used at the time OxyContin was
approved. FDA plans to provide guidance to the pharmaceutical industry
by September 2004 on risk management plans, which are an optional
feature of new drug applications. DEA has established a national
action plan to prevent abuse and diversion of OxyContin. State
agencies have investigated reports of abuse and diversion. In addition
to developing a risk management plan, Purdue has initiated several
OxyContin-related educational programs, taken disciplinary action
against sales representatives who improperly promoted OxyContin, and
referred physicians suspected of improper prescribing practices to the
authorities.
What GAO Recommends:
To improve efforts to prevent or identify abuse and diversion of
controlled substances such as OxyContin, FDA‘s risk management plan
guidance should encourage pharmaceutical manufacturers with new drug
applications to submit plans that contain a strategy for identifying
potential problems with abuse and diversion. FDA concurred with GAO‘s
recommendation. DEA agreed that such risk management plans are
important, and Purdue stated that the report appeared to be fair and
balanced.
www.gao.gov/cgi-bin/getrpt?GAO-04-110.
To view the full product, including the scope and methodology, click
on the link above. For more information, contact Marcia Crosse at
(202) 512-7119.
[End of section]
Contents:
Letter:
Results in Brief:
Background:
Purdue Conducted an Extensive Campaign to Market and Promote
OxyContin:
Several Factors May Have Contributed to OxyContin Abuse and Diversion,
but Relationship to Availability Cannot Be Assessed:
Federal and State Agencies and Purdue Have Taken Actions to Prevent
Abuse and Diversion of OxyContin:
Conclusions:
Recommendation for Executive Action:
Agency and Purdue Comments and Our Evaluation:
Appendix I: Scope and Methodology:
Appendix II: Summary of FDA Changes to the Original Approved OxyContin
Label:
Appendix III: Databases Used to Monitor Abuse and Diversion of
OxyContin and Its Active Ingredient Oxycodone:
DAWN Data:
NFLIS Data:
STRIDE Data:
National Survey on Drug Use and Health Data:
Monitoring the Future Survey Data:
Appendix IV: Comments from the Food and Drug Administration:
Appendix V: Comments from the Drug Enforcement Administration:
Tables:
Table 1: Sales Representative Positions Available for OxyContin
Promotion, 1996 through 2002:
Table 2: Total OxyContin Sales and Prescriptions for 1996 through 2002
with Percentage Increases from Year to Year:
Table 3: Selected Language Approved by FDA in Warning Sections of
OxyContin Labels, 1995 and 2001:
Table 4: Selected Language Approved by FDA in the Indication Sections
of OxyContin Labels, 1995 and 2001:
Table 5: FDA Changes to the Original OxyContin Label Made from June
1996 through July 2001:
Figure:
Figure 1: Promotional Spending for Three Opioid Analgesics in First 6
Years of Sales:
Abbreviations:
DAWN: Drug Abuse Warning Network:
DEA: Drug Enforcement Administration:
FDA: Food and Drug Administration:
FD&C Act: Federal Food, Drug and Cosmetic Act:
HHS: Department of Health and Human Services:
HIDTA: High Intensity Drug Trafficking Area:
JCAHO: Joint Commission on Accreditation of Healthcare Organizations:
NFLIS: National Forensic Laboratory Information System:
ONDCP: Office of National Drug Control Policy:
PDUFA Prescription Drug User Fee Act of 1992:
PhRMA: Pharmaceutical Research and Manufacturers of America:
RADARS: Researched Abuse, Diversion, and Addiction-Related
Surveillance:
SAMHSA: Substance Abuse and Mental Health Services Administration:
STRIDE: System to Retrieve Information from Drug Evidence:
WHO: World Health Organization:
United States General Accounting Office:
Washington, DC 20548:
December 19, 2003:
The Honorable Frank R. Wolf:
Chairman:
Subcommittee on Commerce, Justice, State, and the Judiciary, and
Related Agencies:
Committee on Appropriations:
House of Representatives:
The Honorable James C. Greenwood:
Chairman:
Subcommittee on Oversight and Investigations:
Committee on Energy and Commerce:
House of Representatives:
The Honorable Harold Rogers:
House of Representatives:
Patients with cancer may suffer from fairly constant pain for months or
years. Patients with other diseases or conditions, such as rheumatoid
arthritis, osteoarthritis, chronic back pain, or sickle cell anemia,
may also suffer from pain that lasts for extended periods of time.
Since 1986, the World Health Organization (WHO) and others have
reported that the inadequate treatment of cancer and noncancer pain is
a serious public health concern. To address this concern, efforts have
been made to better educate health care professionals on the need to
improve the treatment of both cancer and noncancer pain, including the
appropriate role of prescription drugs.
Amid the heightened awareness that many people were suffering from
undertreated pain, in 1995 the Food and Drug Administration (FDA)
approved the new drug OxyContin, a controlled-release semisynthetic
opioid analgesic manufactured by Purdue Pharma L.P.,[Footnote 1] for
the treatment of moderate-to-severe pain lasting more than a few
days.[Footnote 2] According to Purdue, OxyContin provides patients with
continuous relief from pain over a 12-hour period, reduces pain
fluctuations, requires fewer daily doses to help patients adhere to
their prescribed regimen more easily, allows them to sleep through the
night, and allows a physician to increase the OxyContin dose for a
patient as needed to relieve pain.[Footnote 3] Sales of the drug
increased rapidly following its introduction to the marketplace in
1996. By 2001, sales had exceeded $1 billion annually, and OxyContin
had become the most frequently prescribed brand-name narcotic
medication for treating moderate-to-severe pain in the United States.
In early 2000, media reports began to surface in several states that
OxyContin was being abused--that is, used for nontherapeutic purposes
or for purposes other than those for which it was prescribed--and
illegally diverted.[Footnote 4] According to FDA and the Drug
Enforcement Administration (DEA), the abuse of OxyContin is associated
with serious consequences, including addiction, overdose, and
death.[Footnote 5] When OxyContin was approved, the federal government
classified it as a schedule II controlled substance under the
Controlled Substances Act because it has a high potential for abuse and
may lead to severe psychological or physical dependence.[Footnote 6]
DEA has characterized the pharmacological effects of OxyContin, and its
active ingredient oxycodone, as similar to those of heroin. Media
reports indicated that abusers were crushing OxyContin tablets and
snorting the powder or dissolving it in water and injecting it to
defeat the intended controlled-release effect of the drug and attain a
"rush" or "high" through the body's rapid absorption of oxycodone.
During a December 2001 congressional hearing, witnesses from DEA and
other law enforcement officials from Kentucky, Virginia, and West
Virginia described the growing problem of abuse and diversion of
OxyContin.[Footnote 7] Questions were raised about what factors may
have caused the abuse and diversion, including whether Purdue's efforts
to market the drug may have contributed to the problem. In February
2002, another congressional hearing was conducted on federal, state,
and local efforts to decrease the abuse and diversion of
OxyContin.[Footnote 8]
Because of your concerns about these issues, you asked us to examine
the marketing and promotion of OxyContin and its abuse and diversion.
Specifically, we addressed the following questions:
1. How has Purdue marketed and promoted OxyContin?
2. What factors contributed to the abuse and diversion of OxyContin?
3. What actions have been taken to address OxyContin abuse and
diversion?
To identify how Purdue marketed and promoted OxyContin, we interviewed
Purdue officials and analyzed company documents and data. We also
interviewed selected Purdue sales representatives who were high and
midrange sales performers during 2001 and physicians who were among the
highest prescribers of OxyContin. To determine how Purdue's marketing
and promotion of OxyContin compared to that of other drugs, we examined
the promotional materials and information related to FDA actions and
interviewed officials from companies that manufacture and market three
other opioid drugs, Avinza, Kadian, and Oramorph SR, that like
OxyContin are classified as schedule II controlled substances.[Footnote
9] Because of their concern about the proprietary nature of the
information, the three companies that market these drugs did not
provide us with the same level of detail about the marketing and
promotion of their drugs as did Purdue. We also examined data from DEA
on promotional expenditures for OxyContin and two other schedule II
controlled substances. To examine what factors may have contributed to
the abuse and diversion of OxyContin, we interviewed officials from
DEA, FDA, and Purdue and physicians who prescribe OxyContin. We also
analyzed IMS Health data on sales of OxyContin nationwide and Purdue's
distribution of sales representatives, as part of an effort to compare
the areas with large sales growth and more sales representatives per
capita with the areas where abuse and diversion problems were
identified. However, limitations on the abuse and diversion data
prevented an assessment of the relationship between the availability of
OxyContin and areas where the drug was abused or diverted. To determine
what actions have been taken to address OxyContin abuse and diversion,
we interviewed FDA officials and examined FDA information regarding the
drug's approval and marketing and promotion. We also interviewed DEA
officials and examined how DEA determined the prevalence of OxyContin
abuse and diversion nationally. In addition, we examined state efforts
to identify those involved in the abuse and diversion of OxyContin. We
also reviewed actions taken by Purdue to address this problem. (See
app. I for a detailed discussion of our methodology.):
We performed our work from August 2002 through October 2003, in
accordance with generally accepted government auditing standards.
Results in Brief:
Purdue conducted an extensive campaign to market and promote OxyContin
using an expanded sales force and multiple promotional approaches to
encourage physicians, including primary care specialists, to prescribe
OxyContin as an initial opioid treatment for noncancer pain. OxyContin
sales and prescriptions grew rapidly following its market introduction
in 1996, with the growth in prescriptions for noncancer pain outpacing
the growth in prescriptions for cancer pain from 1997 through 2002. By
2003, nearly half of all OxyContin prescribers were primary care
physicians. DEA has expressed concern that Purdue's aggressive
marketing of OxyContin focused on promoting the drug to treat a wide
range of conditions to physicians who may not have been adequately
trained in pain management. Purdue has been cited twice by FDA for
using potentially false or misleading medical journal advertisements
for OxyContin that violated the Federal Food, Drug and Cosmetic Act
(FD&C Act), including one advertisement that failed to include warnings
about the potentially fatal risks associated with OxyContin use.
Further, Purdue did not submit an OxyContin promotional video for FDA
review at the time of its initial distribution in 1998, as required by
FDA regulations. Therefore, FDA did not have the opportunity to review
the video at the time of its distribution to ensure that the
information it contained was truthful, balanced, and accurately
communicated. FDA reviewed a similar video in 2002 and told us that the
video appeared to have made unsubstantiated claims about OxyContin and
minimized its risks.
Several factors may have contributed to OxyContin's abuse and
diversion. OxyContin's controlled-release formulation, which made the
drug beneficial for the relief of moderate-to-severe pain over an
extended period of time, enabled the drug to contain more of the active
ingredient oxycodone than other, non-controlled-release oxycodone-
containing drugs. This feature may have made OxyContin an attractive
target for abuse and diversion, according to DEA. OxyContin's
controlled-release formulation, which delayed the drug's absorption,
also led FDA to include language in the original label stating that
OxyContin had a lower potential for abuse than other oxycodone
products. FDA officials thought that the controlled-release feature
would make the drug less attractive to abusers. However, FDA did not
recognize that the drug could be dissolved in water and injected, which
disrupted the controlled-release characteristics and created an
immediate rush or high, thereby increasing the potential for abuse. In
addition, the safety warning on the label that advised patients not to
crush the tablets because a rapid release of a potentially toxic amount
of the drug could result--a customary precaution for controlled-release
medications--may have inadvertently alerted abusers to a possible
method for misusing the drug. The rapid growth in OxyContin sales,
which increased the drug's availability in the marketplace, may have
made it easier for abusers to obtain the drug for illicit purposes.
Further, some geographic areas have been shown to have a history of
prescription drug abuse and diversion that may have predisposed some
states to the abuse and diversion of OxyContin. However, we could not
assess the relationship between the increased availability of OxyContin
and locations where it is being abused and diverted because the data on
abuse and diversion are not reliable, comprehensive, or timely.
Since 2000, federal and state agencies and Purdue have taken several
actions to try to address abuse and diversion of OxyContin. In July
2001, FDA approved a revised OxyContin label adding the highest level
of safety warning that FDA can place on an approved drug product. The
agency also collaborated with Purdue to develop and implement a risk
management plan to help detect and prevent abuse and diversion of
OxyContin. Risk management plans were not used at the time OxyContin
was approved. The plans are an optional feature of new drug
applications that are intended to decrease product risks by using one
or more interventions or tools beyond the approved product labeling.
FDA plans to provide guidance on risk management plans to the
pharmaceutical industry by September 2004. Also at the federal level,
DEA initiated 257 OxyContin-related abuse and diversion cases in fiscal
years 2001 and 2002, which resulted in 302 arrests and about $1 million
in fines. At the state level, Medicaid fraud control units have
investigated OxyContin abuse and diversion; however, they do not
maintain precise data on the number of investigations and enforcement
actions completed. Similarly, state medical licensure boards have
investigated complaints about physicians who were suspected of abuse
and diversion of controlled substances, but they could not provide data
on the number of investigations involving OxyContin. Purdue has
initiated education programs and other activities for physicians,
pharmacists, and the public to address OxyContin abuse and diversion.
Purdue has also taken disciplinary action against its sales
representatives who improperly promoted OxyContin and has referred
physicians who were suspected of misprescribing OxyContin to the
appropriate authorities. Although Purdue has used very specific
information on physician prescribing practices to market and promote
OxyContin since its approval, it was not until October 2002 that Purdue
began to use this information and other indicators to identify patterns
of prescribing that could point to possible improper sales
representative promotion or physician abuse and diversion of OxyContin.
To improve efforts to prevent or identify the abuse and diversion of
schedule II controlled substances such as oxycodone, we recommend that
FDA's risk management plan guidance encourage the pharmaceutical
manufacturers that submit new drug applications for these substances to
include plans that contain a strategy for monitoring the use of these
drugs and identifying potential abuse and diversion problems.
We received comments on a draft of this report from FDA, DEA, and
Purdue. FDA agreed with our recommendation that risk management plans
for schedule II controlled substances contain a strategy for monitoring
and identifying potential abuse and diversion problems. DEA reiterated
its statement that Purdue's aggressive marketing of OxyContin
exacerbated the abuse and diversion problems and noted that it is
essential that risk management plans be put in place prior to the
introduction of controlled substances into the marketplace. Purdue said
the report appeared to be fair and balanced, but that we should add the
media as one of the factors contributing to abuse and diversion
problems with OxyContin. We incorporated their technical comments where
appropriate.
Background:
Ensuring that pharmaceuticals are available for those with legitimate
medical need while combating the abuse and diversion of prescription
drugs involves the efforts of both federal and state government
agencies. Under the FD&C Act, FDA is responsible for ensuring that
drugs are safe and effective before they are available in the
marketplace. The Controlled Substances Act,[Footnote 10] which is
administered by DEA, provides the legal framework for the federal
government's oversight of the manufacture and wholesale distribution of
controlled substances, that is, drugs and other chemicals that have a
potential for abuse. The states address certain issues involving
controlled substances through their own controlled substances acts and
their regulation of the practice of medicine and pharmacy. In response
to concerns about the influence of pharmaceutical marketing and
promotional activities on physician prescribing practices, both the
pharmaceutical industry and the Department of Health and Human
Services's (HHS) Office of Inspector General have issued voluntary
guidelines on appropriate marketing and promotion of prescription
drugs.
Medical Treatment of Pain:
As the incidence and prevalence of painful diseases have grown along
with the aging of the population, there has been a growing
acknowledgment of the importance of providing effective pain relief.
Pain can be characterized in terms of intensity--mild to severe--and
duration--acute (sudden onset) or chronic (long term). The appropriate
medical treatment varies according to these two dimensions.
In 1986, WHO determined that cancer pain could be relieved in most if
not all patients, and it encouraged physicians to prescribe opioid
analgesics. WHO developed a three-step analgesic ladder as a practice
guideline to provide a sequential use of different drugs for cancer
pain management. For the first pain step, treatment with nonopioid
analgesics, such as aspirin or ibuprofen, is recommended. If pain is
not relieved, then an opioid such as codeine should be used for mild-
to-moderate pain as the second step. For the third step--moderate-to-
severe pain--opioids such as morphine should be used.
Beginning in the mid-1990s, various national pain-related organizations
issued pain treatment and management guidelines, which included the use
of opioid analgesics in treating both cancer and noncancer pain. In
1995, the American Pain Society recommended that pain should be treated
as the fifth vital sign[Footnote 11] to ensure that it would become
common practice for health care providers to ask about pain when
conducting patient evaluations. The practice guidelines issued by the
Agency for Health Care Policy and Research provided physicians and
other health care professionals with information on the management of
acute pain in 1992 and cancer pain in 1994, respectively.[Footnote 12]
Health care providers and hospitals were further required to ensure
that their patients received appropriate pain treatment when the Joint
Commission on Accreditation of Healthcare Organizations (JCAHO), a
national health care facility standards-setting and accrediting body,
implemented its pain standards for hospital accreditation in 2001.
OxyContin:
OxyContin, a schedule II drug manufactured by Purdue Pharma L.P., was
approved by FDA in 1995 for the treatment of moderate-to-severe pain
lasting more than a few days, as indicated in the original
label.[Footnote 13] OxyContin followed Purdue's older product, MS
Contin, a morphine-based product that was approved in 1984 for a
similar intensity and duration of pain and during its early years of
marketing was promoted for the treatment of cancer pain. The active
ingredient in OxyContin tablets is oxycodone, a compound that is
similar to morphine and is also found in oxycodone-combination pain
relief drugs such as Percocet, Percodan, and Tylox. Because of its
controlled-release property, OxyContin contains more active ingredient
and needs to be taken less often (twice a day) than these other
oxycodone-containing drugs.[Footnote 14] The OxyContin label
originally approved by FDA indicated that the controlled-release
characteristics of OxyContin were believed to reduce its potential for
abuse. The label also contained a warning that OxyContin tablets were
to be swallowed whole, and were not to be broken, chewed, or crushed
because this could lead to the rapid release and absorption of a
potentially toxic dose of oxycodone. Such a safety warning is customary
for schedule II controlled-release medications. FDA first approved the
marketing and use of OxyContin in 10-, 20-, and 40-milligram
controlled-release tablets. FDA later approved 80-and 160-milligram
controlled-release tablets for use by patients who were already taking
opioids.[Footnote 15] In July 2001, FDA approved the revised label to
state that the drug is approved for the treatment of moderate-to-severe
pain in patients who require "a continuous around-the-clock analgesic
for an extended period of time." (See app. II for a summary of the
changes that were made by FDA to the original OxyContin label.):
OxyContin sales and prescriptions grew rapidly following its market
introduction in 1996. Fortuitous timing may have contributed to this
growth, as the launching of the drug occurred during the national focus
on the inadequacy of patient pain treatment and management. In 1997,
OxyContin's sales and prescriptions began increasing significantly, and
they continued to increase through 2002. In both 2001 and 2002,
OxyContin's sales exceeded $1 billion, and prescriptions were over 7
million. The drug became Purdue's main product, accounting for 90
percent of the company's total prescription sales by 2001.
Media reports of OxyContin abuse and diversion began to surface in
2000. These reports first appeared in rural areas of some states,
generally in the Appalachian region, and continued to spread to other
rural areas and larger cities in several states. Rural communities in
Maine, Kentucky, Ohio, Pennsylvania, Virginia, and West Virginia were
reportedly being devastated by the abuse and diversion of OxyContin.
For example, media reports told of persons and communities that had
been adversely affected by the rise of addiction and deaths related to
OxyContin. One report noted that drug treatment centers and emergency
rooms in a particular area were receiving new patients who were
addicted to OxyContin as early as 1999. Pain patients, teens, and
recreational drug users who had abused OxyContin reportedly entered
drug treatment centers sweating and vomiting from withdrawal. In West
Virginia, as many as one-half of the approximately 300 patients
admitted to a drug treatment clinic in 2000 were treated for OxyContin
addiction. The media also reported on deaths due to OxyContin. For
example, a newspaper's investigation of autopsy reports involving
oxycodone-related deaths found that OxyContin had been involved in over
200 overdose deaths in Florida since 2000.[Footnote 16] In another
case, a forensic toxicologist commented that he had reviewed a number
of fatal overdose cases in which individuals took a large dose of
OxyContin, in combination with alcohol or other drugs.
After learning about the initial reports of abuse and diversion of
OxyContin in Maine in 2000, Purdue formed a response team made up of
its top executives and physicians to initiate meetings with federal and
state officials in Maine to gain an understanding of the scope of the
problem and to devise strategies for preventing abuse and diversion.
After these meetings, Purdue distributed brochures to health care
professionals that described several steps that could be taken to
prevent prescription drug abuse and diversion. In response to the abuse
and diversion reports, DEA analyzed data collected from medical
examiner autopsy reports and crime scene investigation reports. The
most recent data available from DEA show that as of February 2002, the
agency had verified 146 deaths nationally involving OxyContin in 2000
and 2001.
According to Purdue, as of early October 2003, over 300 lawsuits
concerning OxyContin were pending against Purdue, and 50 additional
lawsuits had been dismissed. The cases involve many allegations,
including, for example, that Purdue used improper sales tactics and
overpromoted OxyContin causing the drug to be inappropriately
prescribed by physicians, and that Purdue took inadequate actions to
prevent addiction, abuse, and diversion of the drug. The lawsuits have
been brought in 25 states and the District of Columbia in both federal
and state courts.
Controlled Substances Act:
The Controlled Substances Act established a classification structure
for drugs and chemicals used in the manufacture of drugs that are
designated as controlled substances.[Footnote 17] Controlled
substances are classified by DEA into five schedules on the basis of
their medicinal value, potential for abuse, and safety or dependence
liability. Schedule I drugs--including heroin, marijuana, and LSD--have
a high potential for abuse and no currently accepted medical use.
Schedule II drugs--which include opioids such as morphine and
oxycodone, the primary ingredient in OxyContin--have a high potential
for abuse among drugs with an accepted medical use and may lead to
severe psychological or physical dependence. Drugs on schedules III
through V have medical uses and successively lower potentials for abuse
and dependence. Schedule III drugs include anabolic steroids, codeine,
hydrocodone in combination with aspirin or acetaminophen, and some
barbiturates. Schedule IV contains such drugs as the antianxiety drugs
diazepam (Valium) and alprazolam (Xanax). Schedule V includes
preparations such as cough syrups with codeine. All scheduled drugs
except those in schedule I are legally available to the public with a
prescription.[Footnote 18]
FDA's Regulation of Prescription Drugs:
Under the FD&C Act and implementing regulations, FDA is responsible for
ensuring that all new drugs are safe and effective. FDA reviews
scientific and clinical data to decide whether to approve drugs based
on their intended use, effectiveness, and the risks and benefits for
the intended population, and also monitors drugs for continued safety
after they are in use.
FDA also regulates the advertising and promotion of prescription drugs
under the FD&C Act. FDA carries out this responsibility by ensuring
that prescription drug advertising and promotion is truthful, balanced,
and accurately communicated.[Footnote 19] The FD&C Act makes no
distinction between controlled substances and other prescription drugs
in the oversight of promotional activities. FDA told us that the agency
takes a risk-based approach to enforcement, whereby drugs with more
serious risks, such as opioids, are given closer scrutiny in monitoring
promotional messages and activities, but the agency has no specific
guidance or policy on this approach. The FD&C Act and its implementing
regulations require that all promotional materials for prescription
drugs be submitted to FDA at the time the materials are first
disseminated or used, but it generally is not required that these
materials be approved by FDA before their use. As a result, FDA's
actions to address violations occur after the materials have already
appeared in public. In fiscal year 2002, FDA had 39 staff positions
dedicated to oversight of drug advertising and promotion of all
pharmaceuticals distributed in the United States. According to FDA,
most of the staff focuses on the oversight of promotional
communications to physicians. FDA officials told us that in 2001 it
received approximately 34,000 pieces of promotional material, including
consumer advertisements and promotions to physicians, and received and
reviewed 230 complaints about allegedly misleading advertisements,
including materials directed at health professionals.[Footnote 20]
FDA issues two types of letters to address violations of the FD&C Act:
untitled letters and warning letters. Untitled letters are issued for
violations such as overstating the effectiveness of the drug,
suggesting a broader range of indicated uses than the drug has been
approved for, and making misleading claims because of inadequate
context or lack of balanced information. Warning letters are issued for
more serious violations, such as those involving safety or health
risks, or for continued violations of the act. Warning letters
generally advise a pharmaceutical manufacturer that FDA may take
further enforcement actions, such as seeking judicial remediation,
without notifying the company and may ask the manufacturer to conduct a
new advertising campaign to correct inaccurate impressions left by the
advertisements.
Under the Controlled Substances Act, FDA notifies DEA if FDA is
reviewing a new drug application for a drug that has a stimulant,
depressant, or hallucinogenic effect on the central nervous system and
has abuse potential. FDA performs a medical and scientific assessment
as required by the Controlled Substances Act, and recommends to DEA an
initial schedule level to be assigned to a new controlled substance.
FDA plans to provide guidance to the pharmaceutical industry on the
development, implementation, and evaluation of risk management plans as
a result of the reauthorization of the Prescription Drug User Fee Act
of 1992 (PDUFA).[Footnote 21] FDA expects to issue this guidance by
September 30, 2004. FDA defines a risk management program as a
strategic safety program that is designed to decrease product risks by
using one or more interventions or tools beyond the approved product
labeling. Interventions used in risk management plans may include
postmarketing surveillance, education and outreach programs to health
professionals or consumers, informed consent agreements for patients,
limitations on the supply or refills of products, and restrictions on
individuals who may prescribe and dispense drug products. All drug
manufacturers have the option to develop and submit risk management
plans to FDA as part of their new drug applications.
DEA's Regulation of Controlled Substances:
DEA is the primary federal agency responsible for enforcing the
Controlled Substances Act. DEA has the authority to regulate
transactions involving the sale and distribution of controlled
substances at the manufacturer and wholesale distributor levels. DEA
registers legitimate handlers of controlled substances--including
manufacturers, distributors, hospitals, pharmacies, practitioners, and
researchers--who must comply with regulations relating to drug security
and accountability through the maintenance of inventories and records.
All registrants, including pharmacies, are required to maintain records
of controlled substances that have been manufactured, purchased, and
sold. Manufacturers and distributors are also required to report their
annual inventories of controlled substances to DEA. The data provided
to DEA are available for use in monitoring the distribution of
controlled substances throughout the United States and identifying
retail-level registrants that received unusual quantities of controlled
substances. DEA regulations for schedule II prescription drugs, unlike
those for other prescription drugs, require that each prescription must
be written and signed by the physician and may not be telephoned in to
the pharmacy except in an emergency. Also, a prescription for a
schedule II drug may not be refilled. A physician is required to
provide a new prescription each time a patient obtains more of the
drug. DEA also sets limits on the quantity of schedule II controlled
substances that may be produced in the United States in any given year.
Specifically, DEA sets aggregate production quotas that limit the
production of bulk raw materials used in the manufacture of controlled
substances. DEA determines these quotas based on a variety of data
including sales, production, inventories, and exports. Individual
companies must apply to DEA for manufacturing or procurement quotas for
specific pharmaceutical products. For example, Purdue has a procurement
quota for oxycodone, the principle ingredient in OxyContin, that allows
the company to purchase specified quantities of oxycodone from bulk
manufacturers.
States' Regulation of the Practice of Medicine and Pharmacy and Role in
Monitoring Illegal Use and Diversion of Prescription Drugs:
State laws govern the prescribing and dispensing of prescription drugs
by licensed health care professionals. Each state requires that
physicians practicing in the state be licensed, and state medical
practice laws generally outline standards for the practice of medicine
and delegate the responsibility of regulating physicians to state
medical boards. States also require pharmacists and pharmacies to be
licensed. The regulation of the practice of pharmacy is based on state
pharmacy practice acts and regulations enforced by the state boards of
pharmacy. According to the National Association of Boards of Pharmacy,
all state pharmacy laws require that records of prescription drugs
dispensed to patients be maintained and that state pharmacy boards have
access to the prescription records. State regulatory boards face new
challenges with the advent of Internet pharmacies, because they enable
pharmacies and physicians to anonymously reach across state borders to
prescribe, sell, and dispense prescription drugs without complying with
state requirements.[Footnote 22] In some cases, consumers can purchase
prescription drugs, including controlled substances, such as OxyContin,
from Internet pharmacies without a valid prescription.
In addition to these regulatory boards, 15 states operate prescription
drug monitoring programs as a means to control the illegal diversion of
prescription drugs that are controlled substances. Prescription drug
monitoring programs are designed to facilitate the collection,
analysis, and reporting of information on the prescribing, dispensing,
and use of controlled substances within a state. They provide data and
analysis to state law enforcement and regulatory agencies to assist in
identifying and investigating activities potentially related to the
illegal prescribing, dispensing, and procuring of controlled
substances. For example, physicians in Kentucky can use the program to
check a patient's prescription drug history to determine if the
individual may be "doctor shopping" to seek multiple controlled
substance prescriptions. An overriding goal of prescription drug
monitoring programs is to support both the state laws ensuring access
to appropriate pharmaceutical care by citizens and the state laws
deterring diversion. As we have reported, state prescription drug
monitoring programs offer state regulators an efficient means of
detecting and deterring illegal diversion. However, few states
proactively analyze prescription data to identify individuals,
physicians, or pharmacies that have unusual use, prescribing, or
dispensing patterns that may suggest potential drug diversion or abuse.
Although three states can respond to requests for information within 3
to 4 hours, providing information on suspected illegal prescribing,
dispensing, or doctor shopping at the time a prescription is written or
sold would require states to improve computer capabilities. In
addition, state prescription drug monitoring programs may require
additional legal authority to analyze data proactively.[Footnote 23]
Guidelines for Marketing Drugs to Health Care Professionals:
At the time that OxyContin was first marketed, there were no industry
or federal guidelines for the promotion of prescription drugs.
Voluntary guidelines regarding how drug companies should market and
promote their drugs to health care professionals were issued in July
2002 by the Pharmaceutical Research and Manufacturers of America
(PhRMA). In April 2003, HHS's Office of Inspector General issued
voluntary guidelines for how drug companies should market and promote
their products to federal health care programs. Neither set of
guidelines distinguishes between controlled and noncontrolled
substances.
PhRMA's voluntary code of conduct for sales representatives states that
interactions with health care professionals should be to inform these
professionals about products, to provide scientific and educational
information, and to support medical research and education.[Footnote
24] The question-and-answer section of the code addresses companies'
use of branded promotional items, stating, for example, that golf balls
and sports bags should not be distributed because they are not
primarily for the benefit of patients, but that speaker training
programs held at golf resorts may be acceptable if participants are
receiving extensive training. Purdue adopted the code.
In April 2003, HHS's Office of Inspector General issued final voluntary
guidance for drug companies' interactions with health care
professionals in connection with federal health care programs,
including Medicare and Medicaid. Among the guidelines were cautions for
companies against offering inappropriate travel, meals, and gifts to
influence the prescribing of drugs; making excessive payments to
physicians for consulting and research services; and paying physicians
to switch their patients from competitors' drugs.
Purdue Conducted an Extensive Campaign to Market and Promote OxyContin:
Purdue conducted an extensive campaign to market and promote OxyContin
that focused on encouraging physicians, including those in primary care
specialties, to prescribe the drug for noncancer as well as cancer
pain. To implement its OxyContin campaign, Purdue significantly
increased its sales force and used multiple promotional approaches.
OxyContin sales and prescriptions grew rapidly following its market
introduction, with the growth in prescriptions for noncancer pain
outpacing the growth in prescriptions for cancer pain. DEA has
expressed concern that Purdue marketed OxyContin for a wide variety of
conditions to physicians who may not have been adequately trained in
pain management. Purdue has been cited twice by FDA for OxyContin
advertisements in medical journals that violated the FD&C Act. FDA has
also taken similar actions against manufacturers of two of the three
comparable schedule II controlled substances we examined, to ensure
that their marketing and promotion were truthful, balanced, and
accurately communicated. In addition, Purdue provided two promotional
videos to physicians that, according to FDA appear to have made
unsubstantiated claims and minimized the risks of OxyContin. The first
video was available for about 3 years without being submitted to FDA
for review.
Purdue Focused on Promoting OxyContin for Treatment of Noncancer Pain:
From the outset of the OxyContin marketing campaign, Purdue promoted
the drug to physicians for noncancer pain conditions that can be caused
by arthritis, injuries, and chronic diseases, in addition to cancer
pain. Purdue directed its sales representatives to focus on the
physicians in their sales territories who were high opioid prescribers.
This group included cancer and pain specialists, primary care
physicians, and physicians who were high prescribers of Purdue's older
product, MS Contin. One of Purdue's goals was to identify primary care
physicians who would expand the company's OxyContin prescribing base.
Sales representatives were also directed to call on oncology nurses,
consultant pharmacists, hospices, hospitals, and nursing homes.
From OxyContin's launch until its July 2001 label change, Purdue used
two key promotional messages for primary care physicians and other high
prescribers. The first was that physicians should prescribe OxyContin
for their pain patients both as the drug "to start with and to stay
with." The second contrasted dosing with other opioid pain relievers
with OxyContin dosing as "the hard way versus the easy way" to dose
because OxyContin's twice-a-day dosing was more convenient for
patients.[Footnote 25] Purdue's sales representatives promoted
OxyContin to physicians as an initial opioid treatment for moderate-to-
severe pain lasting more than a few days, to be prescribed instead of
other single-entity opioid analgesics or short-acting combination
opioid pain relievers. Purdue has stated that by 2003 primary care
physicians had grown to constitute nearly half of all OxyContin
prescribers, based on data from IMS Health, an information service
providing pharmaceutical market research. DEA's analysis of physicians
prescribing OxyContin found that the scope of medical specialties was
wider for OxyContin than five other controlled-release, schedule II
narcotic analgesics. DEA expressed concern that this resulted in
OxyContin's being promoted to physicians who were not adequately
trained in pain management.
Purdue's promotion of OxyContin for the treatment of noncancer pain
contributed to a greater increase in prescriptions for noncancer pain
than for cancer pain from 1997 through 2002.[Footnote 26] According to
IMS Health data, the annual number of OxyContin prescriptions for
noncancer pain increased nearly tenfold, from about 670,000 in 1997 to
about 6.2 million in 2002.[Footnote 27] In contrast, during the same 6
years, the annual number of OxyContin prescriptions for cancer pain
increased about fourfold, from about 250,000 in 1997 to just over 1
million in 2002. The noncancer prescriptions therefore increased from
about 73 percent of total OxyContin prescriptions to about 85 percent
during that period, while the cancer prescriptions decreased from about
27 percent of the total to about 15 percent. IMS Health data indicated
that prescriptions for other schedule II opioid drugs, such as
Duragesic[Footnote 28] and morphine products, for noncancer pain also
increased during this period. Duragesic prescriptions for noncancer
pain were about 46 percent of its total prescriptions in 1997, and
increased to about 72 percent of its total in 2002. Morphine products,
including, for example, Purdue's MS Contin, also experienced an
increase in their noncancer prescriptions during the same period. Their
noncancer prescriptions were about 42 percent of total prescriptions in
1997, and increased to about 65 percent in 2002. DEA has cited Purdue's
focus on promoting OxyContin for treating a wide range of conditions as
one of the reasons the agency considered Purdue's marketing of
OxyContin to be overly aggressive.
Purdue Significantly Increased Its Sales Force to Market and Promote
OxyContin:
Purdue significantly increased its sales force to market and promote
OxyContin to physicians and other health care practitioners. In 1996,
Purdue began promoting OxyContin with a sales force of approximately
300 representatives in its Prescription Sales Division.[Footnote 29]
Through a 1996 copromotion agreement, Abbott Laboratories provided at
least another 300 representatives, doubling the total OxyContin sales
force.[Footnote 30] By 2000, Purdue had more than doubled its own
internal sales force to 671. The expanded sales force included sales
representatives from the Hospital Specialty Division, which was created
in 2000 to increase promotional visits on physicians located in
hospitals. (See table 1.):
Table 1: Sales Representative Positions Available for OxyContin
Promotion, 1996 through 2002:
Positions available[A]: Purdue Prescription Sales Division;
1996: 318;
1997: 319;
1998: 377;
1999: 471;
2000: 562;
2001: 641;
2002: 641.
Positions available[A]: Purdue Hospital Specialty Division;
1996: 0;
1997: 0;
1998: 0;
1999: 0;
2000: 109;
2001: 125;
2002: 126.
Positions available[A]: Subtotal--All Purdue sales representatives;
1996: 318;
1997: 319;
1998: 377;
1999: 471;
2000: 671;
2001: 766;
2002: 767.
Positions available[A]: Abbott Laboratories sales representatives[B];
1996: 300;
1997: 300;
1998: 300;
1999: 300;
2000: 300;
2001: 300;
2002: 300.
Positions available[A]: Total;
1996: 618;
1997: 619;
1998: 677;
1999: 771;
2000: 971;
2001: 1,066;
2002: 1,067.
Source: GAO analysis of Purdue data.
[A] All positions were not necessarily filled in a given year.
[B] Under the OxyContin copromotion agreement, Abbott Laboratories
provided at least 300 sales representatives each year.
[End of table]
The manufacturers of two of the three comparable schedule II drugs have
smaller sales forces than Purdue. Currently, the manufacturer of Kadian
has about 100 sales representatives and is considering entering into a
copromotion agreement. Elan, the current owner of Oramorph SR, has
approximately 300 representatives, but told us that it is not currently
marketing Oramorph SR. The manufacturer of Avinza had approximately 50
representatives at its product launch. In early 2003, Avinza's
manufacturer announced that more than 700 additional sales
representatives would be promoting the drug under its copromotion
agreement with the pharmaceutical manufacturer Organon--for a total of
more than 800 representatives.
By more than doubling its total sales representatives, Purdue
significantly increased the number of physicians to whom it was
promoting OxyContin. Each Purdue sales representative has a specific
sales territory and is responsible for developing a list of about 105
to 140 physicians to call on who already prescribe opioids or who are
candidates for prescribing opioids. In 1996, the 300-plus Purdue sales
representatives had a total physician call list of approximately 33,400
to 44,500. By 2000, the nearly 700 representatives had a total call
list of approximately 70,500 to 94,000 physicians. Each Purdue sales
representative is expected to make about 35 physician calls per week
and typically calls on each physician every 3 to 4 weeks. Each hospital
sales representative is expected to make about 50 calls per week and
typically calls on each facility every 4 weeks.
Purdue stated it offered a "better than industry average" salary and
sales bonuses to attract top sales representatives and provide
incentives to boost OxyContin sales as it had done for MS Contin.
Although the sales representatives were primarily focused on OxyContin
promotion, the amount of the bonus depended on whether a representative
met the sales quotas in his or her sales territory for all company
products. As OxyContin's sales increased, Purdue's growth-based portion
of the bonus formula increased the OxyContin sales quotas necessary to
earn the same base sales bonus amounts. The amount of total bonuses
that Purdue estimated were tied to OxyContin sales increased
significantly from about $1 million in 1996, when OxyContin was first
marketed, to about $40 million in 2001. Beginning in 2000, when the
newly created hospital specialty representatives began promoting
OxyContin, their estimated total bonuses were approximately $6 million
annually. In 2001, the average annual salary for a Purdue sales
representative was $55,000, and the average annual bonus was $71,500.
During the same year, the highest annual sales bonus was nearly
$240,000, and the lowest was nearly $15,000. In 2001, Purdue decided to
limit the sales bonus a representative could earn based on the growth
in prescribing of a single physician after a meeting with the U.S.
Attorney for the Western District of Virginia at which the company was
informed of the possibility that a bonus could be based on the
prescribing of one physician.
Purdue Employed Multiple Approaches to Market and Promote OxyContin:
In addition to expanding its sales force, Purdue used multiple
approaches to market and promote OxyContin. These approaches included
expanding its physician speaker bureau and conducting speaker training
conferences, sponsoring pain-related educational programs, issuing
OxyContin starter coupons for patients' initial prescriptions,
sponsoring pain-related Web sites, advertising OxyContin in medical
journals, and distributing OxyContin marketing items to health care
professionals.
In our report on direct-to-consumer advertising, we found that most
promotional spending is targeted to physicians.[Footnote 31] For
example, in 2001, 29 percent of spending on pharmaceutical promotional
activities was related to activities of pharmaceutical sales
representatives directed to physicians, and 2 percent was for journal
advertising--both activities Purdue uses for its OxyContin promotion.
The remaining 69 percent of pharmaceutical promotional spending
involved sampling (55 percent), which is the practice of providing drug
samples during sales visits to physician offices, and direct-to-
consumer advertising (14 percent)--both activities that Purdue has
stated it does not use for OxyContin.
According to DEA's analysis of IMS Health data, Purdue spent
approximately 6 to 12 times more on promotional efforts during
OxyContin's first 6 years on the market than it had spent on its older
product, MS Contin, during its first 6 years, or than had been spent by
Janssen Pharmaceutical Products, L.P., for one of OxyContin's drug
competitors, Duragesic. (See fig. 1.):
Figure 1: Promotional Spending for Three Opioid Analgesics in First 6
Years of Sales:
[See PDF for image]
Note: Dollars are 2002 adjusted.
[End of figure]
During the first 5 years that OxyContin was marketed, Purdue conducted
over 40 national pain management and speaker training conferences,
usually in resort locations such as Boca Raton, Florida, and
Scottsdale, Arizona, to recruit and train health care practitioners for
its national speaker bureau. The trained speakers were then made
available to speak about the appropriate use of opioids, including
oxycodone, the active ingredient in OxyContin, to their colleagues in
various settings, such as local medical conferences and grand round
presentations in hospitals involving physicians, residents, and
interns. Over the 5 years, these conferences were attended by more than
5,000 physicians, pharmacists, and nurses, whose travel, lodging, and
meal costs were paid by the company. Purdue told us that less than 1
percent annually of the physicians called on by Purdue sales
representatives attended these conferences. Purdue told us it
discontinued conducting these conferences in fall 2000. Purdue's
speaker bureau list from 1996 through mid-2002 included nearly 2,500
physicians, of whom over 1,000 were active participants. Purdue has
paid participants a fee for speaking based on the physician's
qualifications; the type of program and time commitment involved; and
expenses such as airfare, hotel, and food. The company currently
marketing the comparable drug Avinza has a physician speaker bureau,
but does not sponsor speaker training and conferences at resort
locations. Kadian's current company does not have a physician speaker
bureau and has not held any conferences.
From 1996, when OxyContin was introduced to the market, to July 2002,
Purdue has funded over 20,000 pain-related educational programs through
direct sponsorship or financial grants. These grants included support
for programs to provide physicians with opportunities to earn required
continuing medical education credits, such as grand round presentations
at hospitals and medical education seminars at state and local medical
conferences. During 2001 and 2002, Purdue funded a series of nine
programs throughout the country to educate hospital physicians and
staff on how to comply with JCAHO's pain standards for hospitals and to
discuss postoperative pain treatment. Purdue was one of only two drug
companies that provided funding for JCAHO's pain management educational
programs.[Footnote 32] Under an agreement with JCAHO, Purdue was the
only drug company allowed to distribute certain educational videos and
a book about pain management; these materials were also available for
purchase from JCAHO's Web site. Purdue's participation in these
activities with JCAHO may have facilitated its access to hospitals to
promote OxyContin.
For the first time in marketing any of its products, Purdue used a
patient starter coupon program for OxyContin to provide patients with a
free limited-time prescription. Unlike patient assistance programs,
which provide free prescriptions to patients in financial need, a
coupon program is intended to enable a patient to try a new drug
through a one-time free prescription. A sales representative
distributes coupons to a physician, who decides whether to offer one to
a patient, and then the patient redeems it for a free prescription
through a participating pharmacy. The program began in 1998 and ran
intermittently for 4 years. In 1998 and 1999, each sales representative
had 25 coupons that were redeemable for a free 30-day supply. In 2000
each representative had 90 coupons for a 7-day supply, and in 2001 each
had 10 coupons for a 7-day supply. Approximately 34,000 coupons had
been redeemed nationally when the program was terminated following the
July 2001 OxyContin label change. The manufacturers of two of the
comparable drugs we examined--Avinza and Kadian--used coupon programs
to introduce patients to their products. Avinza's coupon program
requires patients to make a copayment to cover part of the drug's cost.
Purdue has also used Web sites to provide pain-related information to
consumers and others. In addition to its corporate Web site, which
provides product information, Purdue established the "Partners Against
Pain" Web site in 1997 to provide consumers with information about pain
management and pain treatment options. According to FDA, the Web site
also contained information about OxyContin. Separate sections provide
information for patients and caregivers, medical professionals, and
institutions. The Web site includes a "Find a Doctor" feature to enable
consumers to find physicians who treat pain in their geographic
area.[Footnote 33] As of July 2002, over 33,000 physicians were
included. Ligand, which markets Avinza, one of the comparable drugs,
has also used a corporate Web site to provide product information.
Purdue has also funded Web sites, such as FamilyPractice.com, that
provide physicians with free continuing medical educational programs on
pain management.[Footnote 34] Purdue has also provided funding for Web
site development and support for health care groups such as the
American Chronic Pain Association and the American Academy of Pain
Medicine. In addition, Purdue is one of 28 corporate donors--which
include all three comparable drug companies--listed on the Web site of
the American Pain Society, the mission of which is to improve pain-
related education, treatment, and professional practice. Purdue also
sponsors painfullyobvious.com, which it describes as a youth-focused
"message campaign designed to provide information--and stimulate open
discussions--on the dangers of abusing prescription drugs.":
Purdue also provided its sales representatives with 14,000 copies of a
promotional video in 1999 to distribute to physicians. Entitled From
One Pain Patient to Another: Advice from Patients Who Have Found
Relief, the video was to encourage patients to report their pain and to
alleviate patients' concerns about taking opioids. Purdue stated that
the video was to be used "in physician waiting rooms, as a 'check out'
item for an office's patient education library, or as an educational
tool for office or hospital staff to utilize with patients and their
families." Copies of the video were also available for ordering on the
"Partners Against Pain" Web site from June 2000 through July 2001. The
video did not need to be submitted to FDA for its review because it did
not contain any information about OxyContin. However, the video
included a statement that opioid analgesics have been shown to cause
addiction in less than 1 percent of patients. According to FDA, this
statement has not been substantiated.
As part of its marketing campaign, Purdue distributed several types of
branded promotional items to health care practitioners. Among these
items were OxyContin fishing hats, stuffed plush toys, coffee mugs with
heat-activated messages, music compact discs, luggage tags, and pens
containing a pullout conversion chart showing physicians how to
calculate the dosage to convert a patient to OxyContin from other
opioid pain relievers.[Footnote 35] In May 2002, in anticipation of
PhRMA's voluntary guidance for sales representatives' interactions with
health care professionals, Purdue instructed its sales force to destroy
any remaining inventory of non-health-related promotional items, such
as stuffed toys or golf balls. In early 2003, Purdue began distributing
an OxyContin branded goniometer--a range and motion measurement guide.
According to DEA, Purdue's use of branded promotional items to market
OxyContin was unprecedented among schedule II opioids, and was an
indicator of Purdue's aggressive and inappropriate marketing of
OxyContin.
Another approach Purdue used to promote OxyContin was to place
advertisements in medical journals. Purdue's annual spending for
OxyContin advertisements increased from about $700,000 in 1996 to about
$4.6 million in 2001. All three companies that marketed the comparable
drugs have also used medical journal advertisements to promote their
products.
OxyContin Advertisements Violated the FD&C Act:
Purdue has been cited twice by FDA for using advertisements in
professional medical journals that violated the FD&C Act. In May 2000,
FDA issued an untitled letter to Purdue regarding a professional
medical journal advertisement for OxyContin.[Footnote 36] FDA noted
that among other problems, the advertisement implied that OxyContin had
been studied for all types of arthritis pain when it had been studied
only in patients with moderate-to-severe osteoarthritis pain, the
advertisement suggested OxyContin could be used as an initial therapy
for the treatment of osteoarthritis pain without substantial evidence
to support this claim, and the advertisement promoted OxyContin in a
selected class of patients--the elderly--without presenting risk
information applicable to that class of patients.[Footnote 37] Purdue
agreed to stop dissemination of the advertisement. The second action
taken by FDA was more serious. In January 2003, FDA issued a warning
letter to Purdue regarding two professional medical journal
advertisements for OxyContin that minimized its risks and overstated
its efficacy, by failing to prominently present information from the
boxed warning on the potentially fatal risks associated with OxyContin
and its abuse liability, along with omitting important information
about the limitations on the indicated use of OxyContin.[Footnote 38]
The FDA requested that Purdue cease disseminating these advertisements
and any similar violative materials and provide a plan of corrective
action. In response, Purdue issued a corrected advertisement, which
called attention to the warning letter and the cited violations and
directed the reader to the prominently featured boxed warning and
indication information for OxyContin.[Footnote 39] The FDA letter was
one of only four warning letters issued to drug manufacturers during
the first 8 months of 2003.[Footnote 40]
In addition, in follow-up discussions with Purdue officials on the
January 2003 warning letter, FDA expressed concerns about some of the
information on Purdue's "Partners Against Pain" Web site. The Web site
appeared to suggest unapproved uses of OxyContin for postoperative pain
that may have been inconsistent with OxyContin's labeling and lacked
risk information about the drug. For example, one section of the Web
site did not disclose that OxyContin is not indicated for pain in the
immediate postoperative period--the first 12 to 24 hours following
surgery--for patients not previously taking the drug, because its
safety in this setting has not been established. The Web site also did
not disclose that OxyContin is indicated for postoperative pain in
patients already taking the drug or for use after the first 24 hours
following surgery only if the pain is moderate to severe and expected
to persist for an extended period of time. Purdue voluntarily removed
all sections of the Web site that were of concern to FDA.
FDA has also sent enforcement letters to other manufacturers of
controlled substances for marketing and promotion violations of the
FD&C Act. For example, in 1996, FDA issued an untitled letter to Zeneca
Pharmaceuticals, at the time the promoter of Kadian,[Footnote 41] for
providing information about the drug to a health professional prior to
its approval in the United States. Roxane Laboratories, the
manufacturer of Oramorph SR, was issued four untitled letters between
1993 and 1995 for making misleading and possibly false statements.
Roxane used children in an advertisement even though Oramorph SR had
not been evaluated in children, and a Roxane sales representative
issued a promotional letter to a pharmacist that claimed, among other
things, that Oramorph SR was superior to MS Contin in providing pain
relief. FDA has sent no enforcement letters to Ligand Pharmaceuticals
concerning Avinza.
Purdue Distributed an OxyContin Video without FDA's Review That Appears
to Have Made Unsubstantiated Claims and Minimized Risks:
Beginning in 1998, Purdue, as part of its marketing and promotion of
OxyContin, distributed 15,000 copies of an OxyContin video to
physicians without submitting it to FDA for review. This video,
entitled I Got My Life Back: Patients in Pain Tell Their Story,
presented the pain relief experiences of various patients and the pain
medications, including OxyContin, they had been prescribed. FDA
regulations require pharmaceutical manufacturers to submit all
promotional materials for approved prescription drug products to the
agency at the time of their initial use. Because Purdue did not comply
with this regulation, FDA did not have an opportunity to review the
video to ensure that the information it contained was truthful,
balanced, and accurately communicated. Purdue has acknowledged the
oversight of not submitting the video to FDA for review. In February
2001, Purdue submitted a second version of the video to FDA, which
included information about the 160-milligram OxyContin tablet. FDA did
not review this second version until October 2002, after we inquired
about its content. FDA told us it found that the second version of the
video appeared to make unsubstantiated claims regarding OxyContin's
effect on patients' quality of life and ability to perform daily
activities and minimized the risks associated with the drug.
The 1998 video used a physician spokesperson to describe patients with
different pain syndromes and the limitations that each patient faced in
his or her daily activities. Each patient's pain treatment was
discussed, along with the dose amounts and brand names of the
prescription drugs, including OxyContin, that either had been
prescribed in the past or were being prescribed at that time. The
physician in the videos also stated that opioid analgesics have been
shown to cause addiction in less than 1 percent of patients--a fact
that FDA has stated has not been substantiated. At the end of the
video, the OxyContin label was scrolled for the viewer.
In 2000, Purdue submitted another promotional video to FDA entitled I
Got My Life Back: A Two Year Follow up of Patients in Pain, and it
submitted a second version of this video in 2001, which also included
information on the 160-milligram OxyContin tablet. Purdue distributed
12,000 copies of these videos to physicians. Both versions scrolled the
OxyContin label at the end of the videos. FDA stated that it did not
review either of these videos for enforcement purposes because of
limited resources. Distribution of all four Purdue videos was
discontinued by July 2001, in response to OxyContin's labeling changes,
which required the company to modify all of its promotional materials,
but copies of the videos that had already been distributed were not
retrieved and destroyed.
FDA said that it receives numerous marketing and promotional materials
for promoted prescription drugs and that while every effort is made to
review the materials, it cannot guarantee that all materials are
reviewed because of limited resources and competing priorities. FDA
officials also stated that pharmaceutical companies do not always
submit promotional materials as required by regulations and that in
such instances FDA would not have a record of the promotional pieces.
Several Factors May Have Contributed to OxyContin Abuse and Diversion,
but Relationship to Availability Cannot Be Assessed:
There are several factors that may have contributed to the abuse and
diversion of OxyContin. OxyContin's formulation as a controlled-release
opioid that is twice as potent as morphine may have made it an
attractive target for abuse and diversion. In addition, the original
label's safety warning advising patients not to crush the tablets
because of the possible rapid release of a potentially toxic amount of
oxycodone may have inadvertently alerted abusers to possible methods
for misuse. Further, the rapid growth in OxyContin sales increased the
drug's availability in the marketplace and may have contributed to
opportunities to obtain the drug illicitly. The history of abuse and
diversion of prescription drugs in some geographic areas, such as those
within the Appalachian region, may have predisposed some states to
problems with OxyContin. However, we could not assess the relationship
between the growth in OxyContin prescriptions or increased availability
with the drug's abuse and diversion because the data on abuse and
diversion are not reliable, comprehensive, or timely.
OxyContin's Formulation May Have Made It an Inviting Drug for Abuse and
Diversion:
While OxyContin's potency and controlled-release feature may have made
the drug beneficial for the relief of moderate-to-severe pain over an
extended period of time, DEA has stated that those attributes of its
formulation have also made it an attractive target for abuse and
diversion. According to recent studies, oxycodone, the active
ingredient in OxyContin, is twice as potent as morphine.[Footnote 42]
In addition, OxyContin's controlled-release feature allows a tablet to
contain more active ingredient than other, non-controlled-release
oxycodone-containing drugs.
One factor that may have contributed to the abuse and diversion of
OxyContin was FDA's original decision to label the drug as having less
abuse potential than other oxycodone products because of its
controlled-release formulation. FDA officials said when OxyContin was
approved the agency believed that the controlled-release formulation
would result in less abuse potential because, when taken properly, the
drug would be absorbed slowly, without an immediate rush or high. FDA
officials acknowledged that the initial wording of OxyContin's label
was "unfortunate" but was based on what was known about the product at
that time.
FDA officials told us that abusers typically seek a drug that is
intense and fast-acting. When OxyContin was approved, FDA did not
recognize that if the drug is dissolved in water and injected its
controlled-release characteristics could be disrupted, creating an
immediate rush or high and thereby increasing the potential for misuse
and abuse. DEA officials told us that OxyContin became a target for
abusers and diverters because the tablet contained larger amounts of
active ingredient and the controlled-release formulation was easy for
abusers to compromise.
The safety warning on the OxyContin label may also have contributed to
the drug's potential for abuse and diversion, by inadvertently
providing abusers with information on how the drug could be misused.
The label included the warning that the tablets should not be broken,
chewed, or crushed because such action could result in the rapid
release and absorption of a potentially toxic dose of oxycodone. FDA
places similar safety warnings on other drugs to ensure that they are
used properly. FDA officials stated that neither they nor other experts
anticipated that crushing the controlled-release tablet and
intravenously injecting or snorting the drug would become widespread
and lead to a high level of abuse.
OxyContin's Wide Availability May Have Increased Opportunities for
Illicit Use:
The large amount of OxyContin available in the marketplace may have
increased opportunities for abuse and diversion. Both DEA and Purdue
have stated that an increase in a drug's availability in the
marketplace may be a factor that attracts interest by those who abuse
and divert drugs. Following its market introduction in 1996, OxyContin
sales and prescriptions grew rapidly through 2002. In 2001 and 2002
combined, sales of OxyContin approached $3 billion, and over 14 million
prescriptions for the drug were dispensed. (See table 2.) OxyContin
also became the top-selling brand-name narcotic pain reliever in 2001
and was ranked 15th on a list of the nation's top 50 prescription drugs
by retail sales.[Footnote 43]
Table 2: Total OxyContin Sales and Prescriptions for 1996 through 2002
with Percentage Increases from Year to Year:
Year: 1996;
Sales: $44,790,000;
Percentage increase: N/A;
Number of prescriptions: 316,786;
Percentage increase: N/A.
Year: 1997;
Sales: 125,464,000;
Percentage increase: 180;
Number of prescriptions: 924,375;
Percentage increase: 192.
Year: 1998;
Sales: 286,486,000;
Percentage increase: 128;
Number of prescriptions: 1,910,944;
Percentage increase: 107.
Year: 1999;
Sales: 555,239,000;
Percentage increase: 94;
Number of prescriptions: 3,504,827;
Percentage increase: 83.
Year: 2000;
Sales: 981,643,000;
Percentage increase: 77;
Number of prescriptions: 5,932,981;
Percentage increase: 69.
Year: 2001;
Sales: 1,354,717,000;
Percentage increase: 38;
Number of prescriptions: 7,183,327;
Percentage increase: 21.
Year: 2002;
Sales: 1,536,816,000;
Percentage increase: 13;
Number of prescriptions: 7,234,204;
Percentage increase: 7.
Sources: Purdue and IMS Health.
Legend: N/A = not applicable.
Note: GAO analysis of OxyContin sales and prescription data from Purdue
and IMS Health, which includes data from all 50 states and the District
of Columbia. Sales include combined retail and nonretail sales in
drugstores, hospitals, and long-term-care facilities from the IMS
Health U.S. National Sales database. Prescriptions include retail
pharmacy, long-term-care, and mail-order prescriptions from IMS
Health's National Prescriptions Audit.
[End of table]
History of Prescription Drug Abuse in Some States May Have Predisposed
Them to Problems with OxyContin:
According to DEA, the abuse and diversion of OxyContin in some states
may have reflected the geographic area's history of prescription drug
abuse. The White House Office of National Drug Control Policy (ONDCP)
designates geographic areas with illegal drug trade activities for
allocation of federal resources to link local, state, and federal drug
investigation and enforcement efforts. These areas, known as High-
Intensity Drug Trafficking Areas (HIDTA), are designated by ONDCP in
consultation with the Attorney General, the Secretary of the Treasury,
heads of drug control agencies, and governors in the states
involved.[Footnote 44]
According to a 2001 HIDTA report,[Footnote 45] the Appalachian region,
which encompasses parts of Kentucky, Tennessee, Virginia, and West
Virginia, has been severely affected by prescription drug abuse,
particularly pain relievers, including oxycodone, for many years. Three
of the four states--Kentucky, Virginia, and West Virginia--were among
the initial states to report OxyContin abuse and diversion.
Historically, oxycodone, manufactured under brand names such as
Percocet, Percodan, and Tylox, was among the most diverted prescription
drugs in Appalachia. According to the report, OxyContin has become the
drug of choice of abusers in several areas within the region. The
report indicates that many areas of the Appalachian region are rural
and poverty-stricken, and the profit potential resulting from the
illicit sale of OxyContin may have contributed to its diversion and
abuse. In some parts of Kentucky, a 20-milligram OxyContin tablet,
which can be purchased by legitimate patients for about $2, can be sold
illicitly for as much as $25. The potential to supplement their incomes
can lure legitimate patients into selling some of their OxyContin to
street dealers, according to the HIDTA report.
Limitations on Abuse and Diversion Data Prevent Assessment of the
Relationship with OxyContin's Availability:
The databases DEA uses to track the abuse and diversion of controlled
substances all have limitations that prevent an assessment of the
relationship between the availability of OxyContin and areas where the
drug is being abused or diverted. Specifically, these databases, which
generally do not provide information on specific brand-name drugs such
as OxyContin, are based on data gathered from limited sources in
specific geographic areas and have a significant time lag. As a result,
they do not provide reliable, complete, or timely information that
could be used to identify abuse and diversion of a specific drug.
DEA officials told us that it is difficult to obtain reliable data on
what controlled substances are being abused by individuals and diverted
from pharmacies because available drug abuse and diversion tracking
systems do not capture data on a specific brand-name product or
indicate where a drug product is being abused and diverted on a state
and local level. Because of the time lags in reporting information, the
data reflect a delayed response to any emerging drug abuse and
diversion problem. For example, the Drug Abuse Warning Network (DAWN)
estimates national drug-related emergency department visits or deaths
involving abused drugs using data collected by the Substance Abuse and
Mental Health Services Administration (SAMHSA). The data are collected
from hospital emergency departments in 21 metropolitan areas that have
agreed to voluntarily report drug-abuse-related information from a
sample of patient medical records, and from medical examiners in 42
metropolitan areas.[Footnote 46] However, DAWN cannot make estimates
for rural areas, where initial OxyContin abuse and diversion problems
were reported to be most prevalent, nor does it usually provide drug-
product-specific information, and its data have a lag time of about 1
year. DEA stated that development of enhanced data collection systems
is needed to provide "credible, legally defensible evidence concerning
drug abuse trends in America."[Footnote 47]
DEA relies primarily on reports from its field offices to determine
where abuse and diversion are occurring. DEA officials stated that the
initial areas that experienced OxyContin abuse and diversion problems
included rural areas within 8 states--Alaska, Kentucky, Maine,
Maryland, Ohio, Pennsylvania, Virginia, and West Virginia. In July
2002, DEA told us that it learned that OxyContin abuse and diversion
problems had spread into larger areas of the initial 8 states, as well
as parts of 15 other states, to involve almost half of the 50
states.[Footnote 48] According to DEA officials, while DEA field
offices continue to report OxyContin as a drug of choice among abusers,
OxyContin has not been and is not now considered the most highly abused
and diverted prescription drug nationally.[Footnote 49] OxyContin is
the most abused single-entity prescription product according to those
DEA state and divisional offices that report OxyContin abuse.
Federal and State Agencies and Purdue Have Taken Actions to Prevent
Abuse and Diversion of OxyContin:
Since becoming aware of reports of abuse and diversion of OxyContin,
federal and state agencies and Purdue have taken actions intended to
address these problems. To protect the public health, FDA has
strengthened OxyContin label warnings and requested that Purdue develop
and implement an OxyContin risk management plan. In addition, DEA has
stepped up law enforcement actions to prevent abuse and diversion of
OxyContin. State Medicaid fraud control units have also attempted to
identify those involved in the abuse and diversion of OxyContin. Purdue
has initiated drug abuse and diversion education programs, taken
disciplinary actions against sales representatives who improperly
promote OxyContin, and referred physicians who were suspected of
improperly prescribing OxyContin to the appropriate authorities.
However, until fall 2002 Purdue did not analyze its comprehensive
physician prescribing reports, which it routinely uses in marketing and
promoting OxyContin, and other indicators to identify possible
physician abuse and diversion.
Reports of Abuse and Diversion Led to Label Changes and Other Actions
by FDA:
Reports of abuse and diversion of OxyContin that were associated with
an increasing incidence of addiction, overdose, and death prompted FDA
to revise the drug's label and take other actions to protect the public
health. In July 2001, FDA reevaluated OxyContin's label and made
several changes in an effort to strengthen the "Warnings" section of
the label. FDA added a subsection--"Misuse, Abuse, and Diversion of
Opioids"--to stress that physicians and pharmacists should be alert to
the risk of misuse, abuse, and diversion when prescribing or dispensing
OxyContin. FDA also added a black box warning--the highest level of
warning FDA can place on an approved drug product. FDA highlighted the
language from the original 1995 label--stating that OxyContin is a
schedule II controlled substance with an abuse liability similar to
morphine--by moving it into the black box. Also, while the original
label suggested that taking broken, chewed, or crushed OxyContin
tablets "could lead to the rapid release and absorption of a
potentially toxic dose of oxycodone," a more strongly worded warning in
the black box stated that taking the drug in this manner "leads to
rapid release and absorption of a potentially fatal dose of oxycodone"
(emphasis added). (See table 3.) In addition to the black box warning,
FDA also changed the language in the original label that described the
incidence of addiction inadvertently induced by physician prescribing
as rare if opioids are legitimately used in the management of pain. The
revised label stated that data are not available to "establish the true
incidence of addiction in chronic patients.":
Table 3: Selected Language Approved by FDA in Warning Sections of
OxyContin Labels, 1995 and 2001:
Warning label in 1995: "Warning: OxyContin Tablets are to be swallowed
whole, and are not to be broken, chewed, or crushed. Taking broken,
chewed, or crushed OxyContin Tablets could lead to the rapid release
and absorption of a potentially toxic dose of oxycodone."; Black box
warning in 2001: "Warning: OxyContin is an opioid agonist and a
Schedule II controlled substance with an abuse liability similar to
morphine."; "OxyContin Tablets are to be swallowed whole and are not to
be broken, chewed, or crushed. Taking broken, chewed, or crushed
OxyContin Tablets leads to rapid release and absorption of a
potentially fatal dose of oxycodone." (emphasis added).
Source: FDA-approved label for Purdue's OxyContin.
[End of table]
As mentioned earlier, the indication described in the original label
was also revised to clarify the appropriate time period for which
OxyContin should be prescribed for patients experiencing moderate-to-
severe pain. The language in the 1995 label was changed from "where use
of an opioid analgesic is appropriate for more than a few days" to
"when a continuous, around-the-clock analgesic is needed for an
extended period of time." (See table 4.) A summary of changes made by
FDA to the original OxyContin label is given in appendix II.
Table 4: Selected Language Approved by FDA in the Indication Sections
of OxyContin Labels, 1995 and 2001:
Indication in 1995: "OxyContin Tablets are a controlled-release oral
formulation of oxycodone hydrochloride indicated for the management of
moderate-to-severe pain where use of an opioid analgesic is appropriate
for more than a few days."; Black box indication change in 2001:
"OxyContin Tablets are a controlled-release oral formulation of
oxycodone hydrochloride indicated for the management of moderate-to-
severe pain when a continuous, around-the-clock analgesic is needed for
an extended period of time." (emphasis added).
Source: FDA-approved label for Purdue's OxyContin.
[End of table]
Beginning in early 2001, FDA collaborated with Purdue to develop and
implement a risk management plan to help identify and prevent abuse and
diversion of OxyContin. As a part of the risk management plan in
connection with the labeling changes, Purdue was asked by FDA to revise
all of its promotional materials for OxyContin to reflect the labeling
changes. In August 2001, FDA sent a letter to Purdue stating that all
future promotional materials for OxyContin should prominently disclose
the information contained in the boxed warning; the new warnings that
address misuse, abuse, diversion, and addiction; and the new
precautions and revised indication for OxyContin. Purdue agreed to
comply with this request.
FDA officials told us that it is standard procedure to contact a drug
manufacturer when the agency becomes aware of reports of abuse and
diversion of a drug product so that FDA and the drug manufacturer can
tailor a specific response to the problem. While FDA's experience with
risk management plans is relatively new, agency officials told us that
OxyContin provided the opportunity to explore the use of the plans to
help identify abuse and diversion problems. FDA is currently making
decisions about whether risk management plans will be requested for
selected opioid products. Also, in September 2003, FDA's Anesthetic and
Life Support Drugs Advisory Committee held a public hearing to discuss
its current review of proposed risk management plans for opioid
analgesic drug products to develop strategies for providing patients
with access to pain treatment while limiting the abuse and diversion of
these products.
FDA has also taken other actions to address the abuse and diversion of
OxyContin. It put information on its Web site for patients regarding
the appropriate use of OxyContin.[Footnote 50] FDA worked with Purdue
to develop "Dear Health Care Professional" letters, which the company
distributed widely to health care professionals to alert them that the
package insert had been revised to clarify the indication and
strengthen the warnings related to misuse, abuse, and diversion. FDA
also has worked with DEA, SAMHSA, the National Institute on Drug Abuse,
ONDCP, and the Centers for Disease Control and Prevention to share
information and insights on the problem of abuse and diversion of
OxyContin.
DEA Developed an Action Plan to Deter OxyContin Abuse and Diversion:
In April 2001, DEA developed a national action plan to deter abuse and
diversion of OxyContin. According to DEA officials, this marked the
first time the agency had targeted a specific brand-name product for
monitoring because of the level and frequency of abuse and diversion
associated with the drug. Key components of the action plan include
coordinating enforcement and intelligence operations with other law
enforcement agencies to target people and organizations involved in
abuse and diversion of OxyContin, pursuing regulatory and
administrative action to limit abusers' access to OxyContin, and
building national outreach efforts to educate the public on the dangers
related to the abuse and diversion of OxyContin. DEA has also set
Purdue's procurement quota for oxycodone at levels lower than the
levels requested by Purdue.
DEA has increased enforcement efforts to prevent abuse and diversion of
OxyContin. From fiscal year 1996 through fiscal year 2002, DEA
initiated 313 investigations involving OxyContin, resulting in 401
arrests. Most of the investigations and arrests occurred after the
initiation of the action plan. Since the plan was enacted, DEA
initiated 257 investigations and made 302 arrests in fiscal years 2001
and 2002. Among those arrested were several physicians and pharmacists.
Fifteen health care professionals either voluntarily surrendered their
controlled substance registrations or were immediately suspended from
registration by DEA. In addition, DEA reported that $1,077,500 in fines
was assessed and $742,678 in cash was seized by law enforcement
agencies in OxyContin-related cases in 2001 and 2002.
Among several regulatory and administrative actions taken to limit
abusers' access to OxyContin and controlled substances, DEA's Office of
Diversion Control, in collaboration with the Department of Justice's
Office of Justice Programs, Bureau of Justice Assistance, provides
grants to states for the establishment of prescription drug monitoring
programs. The conference committee report for the fiscal year 2002
appropriation to the Department of Justice directed the Office of
Justice Programs to make a $2 million grant in support of the Harold
Rogers Prescription Drug Monitoring Program, which enhances the
capacity of regulatory and law enforcement agencies to collect and
analyze controlled substance prescription data. The program provided
grants to establish new monitoring programs in Ohio, Pennsylvania,
Virginia, and West Virginia. California, Kentucky, Massachusetts,
Nevada, and Utah also received grants to enhance existing monitoring
programs.
DEA has also attempted to raise national awareness of the dangers
associated with abuse and diversion of OxyContin. In October 2001 DEA
joined 21 national pain and health organizations in issuing a consensus
statement calling for a balanced policy on prescription medication use.
According to the statement, such a policy would acknowledge that health
care professionals and DEA share responsibility for ensuring that
prescription medications, such as OxyContin, are available to patients
who need them and for preventing these drugs from becoming a source of
abuse and diversion. DEA and the health organizations also called for a
renewed focus on educating health professionals, law enforcement, and
the public about the appropriate use of opioid pain medications in
order to promote responsible prescribing and limit instances of abuse
and diversion. DEA is also working with FDA to encourage state medical
boards to require, as a condition of their state licensing, that
physicians obtain continuing medical education on pain management.
When OxyContin was first introduced to the market in 1996, DEA granted
Purdue's initial procurement quota request for oxycodone. According to
DEA, increases in the quota were granted for the first several years.
Subsequently, concern over the dramatic increases in sales caused DEA
to request additional information to support Purdue's requests to
increase the quota. In the last several years, DEA has taken the
additional step of lowering the procurement quota requested by Purdue
for the manufacture of OxyContin as a means for addressing abuse and
diversion. However, DEA has cited the difficulty of determining an
appropriate level while ensuring that adequate quantities were
available for legitimate medical use, as there are no direct measures
available to establish legitimate medical need.
State Agencies Have Responded to Reports of OxyContin Abuse and
Diversion:
State Medicaid fraud control units and medical licensure boards have
taken action in response to reports of abuse and diversion of
OxyContin. State Medicaid fraud control units have conducted
investigations of abuse and diversion of OxyContin, but generally do
not maintain precise data on the number of investigations and
enforcement actions completed. Although complete information was not
available from directors of state Medicaid fraud control units in
Kentucky, Maryland, Pennsylvania, Virginia, and West Virginia with whom
we spoke, each of those directors told us that abuse and diversion of
OxyContin is a problem in his or her state. The directors told us that
they had investigated cases that involved physicians or individuals who
had either been indicted or prosecuted for writing medically
unnecessary OxyContin prescriptions in exchange for cash or sexual
relationships.
State medical licensure boards have also responded to complaints about
physicians who were suspected of abuse and diversion of controlled
substances, but like the Medicaid fraud control units, the boards
generally do not maintain data on the number of investigations that
involved OxyContin. Representatives of state boards of medicine in
Kentucky, Pennsylvania, Virginia, and West Virginia told us that they
have received complaints from various sources, such as government
agencies, health care professionals, and anonymous tipsters, about
physicians suspected of abuse and diversion of controlled substances.
However, each of the four representatives stated that his or her board
does not track the complaints by specific drug type and consequently
cannot determine whether the complaints received allege physicians'
misuse of OxyContin. Each of the four representatives also told us that
his or her medical licensure board has adopted or strengthened
guidelines or regulations for physicians on prescribing, administering,
and dispensing controlled substances in the treatment of chronic pain.
For example, in March 2001, the Kentucky Board of Medical Licensure
adopted guidelines to clarify the board's position on the use of
controlled substances for nonterminal/nonmalignant chronic
pain.[Footnote 51] The boards of medicine in Pennsylvania, Virginia,
and West Virginia each have guidelines for the appropriate use of
controlled substances that are similar to those adopted by Kentucky.
Purdue Is Implementing a Risk Management Plan for OxyContin:
In response to concerns about abuse and diversion of OxyContin, in
April 2001 FDA and Purdue began to discuss the development of a risk
management plan to help detect and prevent abuse and diversion of
OxyContin. Purdue submitted its risk management plan to FDA for review
in August 2001.[Footnote 52] The plan includes some actions that Purdue
proposed to take, as well as others that it has already taken. Purdue's
risk management plan includes actions such as strengthening the safety
warnings on OxyContin's label for professionals and patients, training
Purdue's sales force on the revised label, conducting comprehensive
education programs for health care professionals, and developing a
database for identifying and monitoring abuse and diversion of
OxyContin.
Under the risk management plan, OxyContin's label was strengthened,
effective in July 2001, by revising the physician prescribing
information and adding a black box warning to call attention to
OxyContin's potential for misuse, abuse, and diversion. (See app. II.)
Purdue trained its sales force on the specifics of the revised label
and provided sales representatives with updated information on the
appropriate use of opioid analgesics, legal guidelines associated with
promotion of its products, and their responsibility and role in
reporting adverse events. Purdue also reiterated to its sales
representatives that failure to promote products according to the
approved label, promotional materials, and applicable FDA standards
would result in disciplinary action by the company. According to
Purdue, from April 2001 through May 2003 at least 10 Purdue employees
were disciplined for using unapproved materials in promoting OxyContin.
Disciplinary actions included warning letters, suspension without pay,
and termination.
Purdue also has provided education programs for health care
professionals and the public under its risk management plan. For
example, in 2001 Purdue supported seminars that examined ways health
care professionals can help prevent abuse and diversion of opioids.
Purdue worked with DEA and other law enforcement agencies to develop
and implement antidiversion educational programs. In 2002, Purdue also
launched the Web site painfullyobvious.com to educate teenagers,
parents, law enforcement officers, and discussion leaders about the
dangers of prescription drug abuse.
Because reliable data on the abuse and diversion of controlled
substance drugs are not available, Purdue developed the Researched
Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System,
as part of its risk management plan, to study the nature and extent of
abuse of OxyContin and other schedule II and III prescription
medications and to implement interventions to reduce abuse and
diversion.[Footnote 53] According to Purdue, RADARS collects and
computes abuse, diversion, and addiction rates for certain drugs based
on population and determines national and local trends.
Since the launch of OxyContin, Purdue has provided its sales force with
considerable information to help target physicians and prioritize sales
contacts within a sales territory. Sales representatives routinely
receive daily, weekly, monthly, and quarterly physician prescribing
reports based on IMS Health data that specify the physicians who have
written prescriptions for OxyContin and other opioid analgesics, and
the number of prescriptions written. Although this information has
always been available for use by Purdue and its sales representatives,
it was not until fall 2002 that Purdue directed its sales
representatives to begin using 11 indicators to identify possible abuse
and diversion and to report the incidents to Purdue's General Counsel's
Office for investigation. Among the possible indicators are a sudden
unexplained change in a physician's prescribing patterns that is not
accounted for by changes in patient numbers, information from credible
sources such as a pharmacist that a physician or his or her patients
are diverting medications, or a physician who writes a large number of
prescriptions for patients who pay with cash. As of September 2003,
Purdue--through its own investigations--had identified 39 physicians
and other health care professionals who were referred to legal,
medical, or regulatory authorities for further action. Most of the 39
referrals stemmed from reports by Purdue's sales force.
Other actions included in the plan that were taken by Purdue prior to
submission of its risk management plan include discontinuance of the
160-milligram tablet of OxyContin to reduce the risk of overdose from
this dosage strength, the development of unique markings for OxyContin
tablets intended for distribution in Mexico and Canada to assist law
enforcement in identifying OxyContin illegally smuggled into the United
States, and the distribution of free tamper-resistant prescription pads
designed to prevent altering or copying of the prescription. Purdue
also implemented a program in 2001 to attempt to predict "hot spots"
where OxyContin abuse and diversion were likely to occur, but
discontinued the program in 2002 when Purdue concluded that nearly two-
thirds of the counties identified had no abuse and diversion.
Conclusions:
At present, both federal agencies and the states have responsibilities
involving prescription drugs and their abuse and diversion. FDA is
responsible for approving new drugs and ensuring that the materials
drug companies use to market and promote these drugs are truthful,
balanced, and accurate. However, FDA examines these promotional
materials only after they have been used in the marketplace because the
FD&C Act generally does not give FDA authority to review these
materials before the drug companies use them. Moreover, the FD&C Act
provisions governing drug approval and promotional materials make no
distinction between controlled substances, such as OxyContin, and other
prescription drugs. DEA is responsible for registering handlers of
controlled substances, approving production quotas and monitoring
distribution of controlled substances to the retail level. It is the
states, however, that are responsible for overseeing the practice of
medicine and pharmacy where drugs are prescribed and dispensed. Some
states have established prescription drug monitoring programs to help
them detect and deter abuse and diversion. However, these programs
exist in only 15 states and most do not proactively analyze
prescription data to identify individuals, physicians, or pharmacies
that have unusual use, prescribing, or dispensing patterns that may
suggest potential drug diversion or abuse.
The significant growth in the use of OxyContin to treat patients
suffering from chronic pain has been accompanied by widespread reports
of abuse and diversion that have in some cases led to deaths. The
problem of abuse and diversion has highlighted shortcomings at the time
of approval in the labeling of schedule II controlled substances, such
as OxyContin, and in the plans in place to detect misuse, as well as in
the infrastructure for detecting and preventing the abuse and diversion
of schedule II controlled substances already on the market.
Addressing abuse and diversion problems requires the collaborative
efforts of pharmaceutical manufacturers; the federal and state agencies
that oversee the approval and use of prescription drugs, particularly
controlled substances; the health care providers who prescribe and
dispense them; and law enforcement. After the problems with OxyContin
began to surface, FDA and Purdue collaborated on a risk management plan
to help detect and prevent abuse and diversion. Although risk
management plans were not in use when OxyContin was approved, they are
now an optional feature of new drug applications. FDA plans to complete
its guidance to the pharmaceutical industry on risk management plans by
September 30, 2004. The development of this guidance, coupled with
FDA's current review of proposed risk management plans for modified-
release opioid analgesics, provides an opportunity to help ensure that
manufacturers include a strategy to monitor the use of these drugs and
to identify potential problems with abuse and diversion.
Recommendation for Executive Action:
To improve efforts to prevent or identify the abuse and diversion of
schedule II controlled substances, we recommend that the Commissioner
of Food and Drugs ensure that FDA's risk management plan guidance
encourages pharmaceutical manufacturers that submit new drug
applications for these substances to include plans that contain a
strategy for monitoring the use of these drugs and identifying
potential abuse and diversion problems.
Agency and Purdue Comments and Our Evaluation:
We provided a draft of this report to FDA, DEA, and Purdue, the
manufacturer of OxyContin, for their review. FDA and DEA provided
written comments. (See apps. IV and V.) Purdue's representatives
provided oral comments.
FDA said that it agreed with our recommendation that its risk
management plan guidance should encourage all pharmaceutical
manufacturers submitting new drug applications for schedule II
controlled substances to include strategies to address abuse and
diversion concerns. FDA stated that the agency is working on the risk
management plan guidance. FDA also noted that the FD&C Act makes no
distinction between controlled substances and other prescription drugs
in its provisions regulating promotion, but that as a matter of general
policy, the agency more closely scrutinizes promotion of drugs with
more serious risk profiles. However, FDA does not have written guidance
that specifies that promotional materials for controlled substances
receive priority or special attention over similar materials for other
prescription drugs. Furthermore, our finding that FDA did not review
any of the OxyContin promotional videos provided by Purdue until we
brought them to the agency's attention raises questions about whether
FDA provides extra attention to promotional materials for controlled
substances that by definition have a high potential for abuse and may
lead to severe psychological or physical dependence. FDA recommended
that we clarify our description of the content of the warning letter
issued to Purdue and provide additional information describing the
extent of the corrective action taken by Purdue. FDA also recommended
noting in the report that part of the risk management plan in
connection with the 2001 labeling changes was a requirement that all
OxyContin promotional materials be revised to reflect the labeling
changes and all future materials prominently disclose this information.
Finally, FDA noted that the promotional videos discussed in the report
were submitted by Purdue prior to the labeling change and discontinued
as a result of the labeling change. As we note in the report, Purdue
acknowledged that all the promotional videos were not submitted to FDA
at the time they were distributed. Moreover, although Purdue told us
that these videos were no longer distributed after the label change,
those videos that had been distributed were not collected and
destroyed. We revised the report to reflect FDA's general comments. FDA
also provided technical comments that we incorporated where
appropriate.
In its written comments, DEA agreed that the data on abuse and
diversion are not reliable, comprehensive, or timely, as we reported.
DEA reiterated its previous statement that Purdue's aggressive
marketing of OxyContin fueled demand for the drug and exacerbated the
drug's abuse and diversion. DEA also stated that Purdue minimized the
abuse risk associated with OxyContin. We agree with DEA that Purdue
conducted an extensive campaign to market and promote OxyContin using
an expanded sales force and multiple promotional approaches to
encourage physicians, including primary care specialists, to prescribe
OxyContin as an initial opioid treatment for noncancer pain, and that
these efforts may have contributed to the problems with abuse and
diversion by increasing the availability of the drug in the
marketplace. However, we also noted that other factors may have
contributed to these problems. We also agree that Purdue marketed
OxyContin as having a low abuse liability, but we noted that this was
based on information in the original label approved by FDA. DEA also
acknowledged that the lack of a real measure of legitimate medical need
for a specific product (OxyContin), substance (oxycodone), or even a
class of substances (controlled release opioid analgesics) makes it
difficult to limit manufacturing as a means of deterring abuse and
diversion. DEA also noted that it is essential that risk management
plans be put in place prior to the introduction of controlled
substances into the marketplace, consistent with our recommendation. We
revised the report to provide some additional detail on problems
associated with OxyContin and Purdue's marketing efforts. DEA provided
some technical comments on the draft report that we incorporated where
appropriate.
Purdue representatives provided oral comments on a draft of this
report. In general, they thought the report was fair and balanced;
however, they offered both general and technical comments.
Specifically, Purdue stated that the report should add the media as a
factor contributing to the abuse and diversion of OxyContin because
media stories provided the public with information on how to "get high"
from using OxyContin incorrectly. Our report notes that the safety
warning on the original label may have inadvertently alerted abusers to
a possible method for misusing the drug. However, we note that the
original label was publicly available from FDA once OxyContin was
approved for marketing. Purdue also suggested that we include
Duragesic, also a schedule II opioid analgesic, as a fourth comparable
drug to OxyContin. The three comparable drugs we used in the report
were chosen in consultation with FDA as comparable opioid analgesics to
OxyContin, because they were time-released, morphine-based schedule II
drugs formulated as tablets like OxyContin. In contrast, Duragesic,
which contains the opioid analgesic fentanyl and provides pain relief
over a 72-hour period, is formulated as a skin patch to be worn rather
than as a tablet. Purdue representatives also provided technical
comments that were incorporated where appropriate.
We also provided sections of this draft report to the manufacturers of
three comparative drugs we examined. Two of the three companies with a
drug product used as a comparable drug to OxyContin reviewed the
portions of the draft report concerning their own product, and provided
technical comments, which were incorporated where appropriate. The
third company did not respond to our request for comments.
As agreed with your offices, unless you publicly announce this report's
contents earlier, we plan no further distribution until 30 days after
its issue date. At that time, we will send copies of this report to the
Commissioner of Food and Drugs, the Administrator of the Drug
Enforcement Administration, Purdue, and the other pharmaceutical
companies whose drugs we examined. We will also make copies available
to others upon request. In addition, the report will be available at no
charge on the GAO Web site at http://www.gao.gov.
If you or your staffs have any questions about this report, please call
me at (202) 512-7119 or John Hansen at (202) 512-7105. Major
contributors to this report were George Bogart, Darryl Joyce, Roseanne
Price, and Opal Winebrenner.
Marcia Crosse:
Director, Health Care--Public Health and Military Health Care Issues:
Signed by Marcia Crosse:
[End of section]
Appendix I: Scope and Methodology:
To identify the strategies and approaches used by Purdue Pharma L.P.
(Purdue) to market and promote OxyContin, we interviewed Purdue
officials and analyzed company documents and data. Specifically, we
interviewed Purdue officials concerning its marketing and promotional
strategies for OxyContin, including its targeting of physicians with
specific specialties and its sales compensation plan to provide sales
representatives with incentives for the drug's sales. We also
interviewed selected Purdue sales representatives who had high and
midrange sales during 2001 from Kentucky, Pennsylvania, Virginia, and
West Virginia--four states that were initially identified by the Drug
Enforcement Agency (DEA) as having a high incidence of OxyContin drug
abuse and diversion--and from California, Massachusetts, and New
Jersey--three states that DEA did not initially identify as having
problems with OxyContin. We asked the sales representatives about their
training, promotional strategies and activities, and targeting of
physicians. We also interviewed physicians who were among the highest
prescribers of OxyContin regarding their experiences with Purdue sales
representatives, including the strategies used to promote OxyContin, as
well as their experiences with sales representatives of manufacturers
of other opioid analgesics. We reviewed Purdue's quarterly action plans
for marketing and promoting OxyContin for 1996 through 2003, Purdue's
sales representative training materials, and materials from ongoing
OxyContin-related litigation. To obtain information on how Purdue's
marketing and promotion of OxyContin compared to that of other
companies, we identified, in consultation with the Food and Drug
Administration (FDA), three opioid analgesics that were similar to
OxyContin. The three drugs--Avinza, Kadian, and Oramorph SR--are all
time-released, morphine-based analgesics that are classified as
schedule II controlled substances. We examined the promotional
materials each drug's manufacturer submitted to FDA and any actions FDA
had taken against the manufacturers related to how the drugs were
marketed or promoted. We also interviewed company officials about how
they marketed and promoted their respective drugs. Because of their
concerns about proprietary information, the three companies did not
provide us with the same level of detail about their drugs' marketing
and promotion as did Purdue.
To examine factors that contributed to the abuse and diversion of
OxyContin, we reviewed DEA abuse and diversion data as part of an
effort to compare them with DEA's OxyContin state distribution data and
with IMS Health data on the rates of OxyContin sales and prescription
dispensing to determine if they occurred in similar geographic areas.
We also analyzed the distribution of Purdue sales representatives by
state and compared them with the availability of OxyContin and abuse
and diversion data to determine whether states with high rates of
OxyContin sales and prescription dispensing and abuse and diversion
problems had more sales representatives per capita than other states.
However, limitations in the abuse and diversion data prevent an
assessment of the relationship between the availability of OxyContin
and areas where the drug was abused and diverted. We also reviewed the
High Intensity Drug Trafficking Area (HIDTA) reports on states with
histories of illegal drug activities. We interviewed DEA and FDA
officials, physicians who prescribed OxyContin, officials from
physician licensing boards in selected states, officials from national
health practitioner groups, and company officials and sales
representatives about why OxyContin abuse and diversion have occurred.
To determine the efforts federal and state agencies and Purdue have
made to identify and prevent abuse and diversion of controlled
substances such as OxyContin, we interviewed FDA officials and analyzed
information from FDA regarding the marketing and promotion of
controlled substances, specifically OxyContin; FDA's decision to
approve the original label for OxyContin; and FDA's subsequent decision
to revise OxyContin's labeling, as well as FDA's role in monitoring
OxyContin's marketing and advertising activities. We also interviewed
DEA officials about the agency's efforts to identify and prevent abuse
and diversion, including its national action plan for OxyContin, and
how it determines the prevalence of OxyContin abuse and diversion
nationally. We also interviewed officials from national practitioner
associations, Medicaid fraud control units, and physician licensing
boards in states with initial reports of abuse and diversion--Kentucky,
Maryland, Pennsylvania, Virginia, and West Virginia--regarding
concerns they had about the abuse and diversion of OxyContin. We
reviewed Purdue's OxyContin risk management plan submissions to FDA
from 2001 through 2003 to identify actions taken by Purdue to address
abuse and diversion of OxyContin.
[End of section]
Appendix II: Summary of FDA Changes to the Original Approved OxyContin
Label:
Table 5 provides a description of the changes made by FDA to sections
of the original OxyContin approved label from June 1996 through July
2001. These changes included a black box warning, the strongest warning
an FDA-approved drug can carry, and specifically addressed areas of
concern related to the opioid characteristics of oxycodone and its risk
of abuse and diversion.
Table 5: FDA Changes to the Original OxyContin Label Made from June
1996 through July 2001:
Summary of FDA changes to original OxyContin label in 2001: Black box
warning was added to stress the opioid nature of oxycodone and risks
for abuse and diversion of the drug;
Language in OxyContin label approved in 2001:
"WARNING: OxyContin is an opioid agonist and a Schedule II controlled
substance with an abuse liability similar to morphine;
Oxycodone can be abused in a manner similar to other opioid agonists,
legal or illicit. This should be considered when prescribing or
dispensing OxyContin in situations where the physician or pharmacist
is concerned about an increased risk of misuse, abuse, or diversion;
OxyContin Tablets are a controlled-release oral formulation of
oxycodone hydrochloride indicated for the management of moderate to
severe pain when a continuous, around-the-clock analgesic is needed
for an extended period of time;
OxyContin Tablets are NOT intended for use as a prn analgesic.
OxyContin 80 mg and 160 mg Tablets ARE FOR USE IN OPIOID-TOLERANT
PATIENTS ONLY. These tablet strengths may cause fatal respiratory
depression when administered to patients not previously exposed to
opioids. OxyContin TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE
BROKEN, CHEWED, OR CRUSHED. TAKING BROKEN, CHEWED, OR CRUSHED
OxyContin TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A
POTENTIALLY FATAL DOSE OF OXYCODONE.".
Summary of FDA changes to original OxyContin label in 2001: Clinical
pharmacology;
--Provides a pharmacological description of oxycodone as a pure opioid
agonist whose principal action is analgesia;
-- Identifies other members of the opioid agonist class, such as
morphine, hydromorphone, fentanyl, and hydrocodone;
--Describes the pharmacological properties of opioids in general
(anxiolysis, euphoria, feelings of relaxation, respiratory depression,
constipation, miosis, cough suppression, and analgesia);
--Describes respiratory depression as one of the most serious side
effects of opioids that could lead to overdose or death;
Language in OxyContin label approved in 2001:
"CLINICAL PHARMACOLOGY;
Oxycodone is a pure agonist opioid whose principal therapeutic action
is analgesia. Other members of the class known as opioid agonists
include substances such as morphine, hydromorphone, fentanyl, codeine,
and hydrocodone. Pharmacological effects of opioid agonists include
anxiolysis, euphoria, feelings of relaxation, respiratory depression,
constipation, miosis, and cough suppression, as well as analgesia.
Like all pure opioid agonist analgesics, with increasing doses there
is increasing analgesia, unlike with mixed agonist/antagonists or non-
opioid analgesics, where there is a limit to the analgesic effect with
increasing doses. With pure opioid agonist analgesics, there is no
defined maximum dose;
the ceiling to analgesic effectiveness is imposed only by side
effects, the more serious of which may include somnolence and
respiratory depression.".
Summary of FDA changes to original OxyContin label in 2001: Misuse,
abuse, and diversion of opioids;
A subsection on misuse, abuse and diversion was added to the WARNINGS
section of the label;
-- Characterizes oxycodone as an opioid agonist of the morphine-type
and stresses that opioid agonists are sought by drug abusers and
people with addiction disorders and are subject to diversion;
--Makes clear that oxycodone can be abused in a manner similar to
other opioid agonists, legal or illicit, and that physicians and
pharmacists should be aware of and alert to risk of misuse, abuse, and
diversion when prescribing or dispensing oxycodone;
--Modifies original label statement that iatrogenic addiction
(addiction induced inadvertently by a physician or a physician's
treatment) is rare if opioids were legitimately used in the management
of pain to state that data are not available to establish the true
incidence of addiction in chronic patients;
Language in OxyContin label approved in 2001:
"Misuse, Abuse and Diversion of Opioids;
Oxycodone is an opioid agonist of the morphine-type. Such drugs are
sought by drug abusers and people with addiction disorders and are
subject to criminal diversion;
Oxycodone can be abused in a manner similar to other opioid agonists,
legal or illicit. This should be considered when prescribing or
dispensing OxyContin in situations where the physician or pharmacist
is concerned about an increased risk of misuse, abuse, or diversion;
OxyContin has been reported as being abused by crushing, chewing,
snorting, or injecting the dissolved product. These practices will
result in the uncontrolled delivery of the opioid and pose a
significant risk to the abuser that could result in overdose and death
(see WARNINGS and DRUG ABUSE AND ADDICTION);
Concerns about abuse, addiction, and diversion should not prevent the
proper management of pain. The development of addiction to opioid
analgesics in properly managed patients with pain has been reported to
be rare. However, data are not available to establish the true
incidence of addiction in chronic pain patients;
Healthcare professionals should contact their State Professional
Licensing Board, or State Controlled Substances Authority for
information on how to prevent and detect abuse of this product.".
Summary of FDA changes to original OxyContin label in 2001: Drug abuse
and addiction;
--Emphasizes that the abuse potential of oxycodone is equivalent to
that of morphine;
--Describes the controlled status of OxyContin and emphasizes that,
like morphine and other opioids used in analgesia, oxycodone can be
abused and is subject to criminal diversion;
--Stresses proper prescribing practices, dispensing, and storage;
--Deletes statement that delayed absorption of OxyContin was believed
to reduce the abuse liability of the drug;
--Stresses the risks associated with parenteral injection of OxyContin
and reiterates the original label's description of drug addiction and
"drug-seeking" behaviors commonly in addicts and abusers;
Language in OxyContin label approved in 2001:
"DRUG ABUSE AND ADDICTION;
OxyContin is a mu-agonist with an abuse liability similar to morphine
and is a Schedule II controlled substance. Oxycodone, like morphine
and other opioids used in analgesia, can be abused and is subject to
criminal diversion;
Drug addiction is characterized by compulsive use, use for non-medical
purposes, and continued use despite harm or risk of harm. Drug
addiction is a treatable disease, utilizing a multi-disciplinary
approach, but relapse is common;
"Drug-seeking" behavior is very common in addicts and drug abusers.
Drug-seeking tactics include emergency calls or visits near the end of
office hours, refusal to undergo appropriate examination, testing or
referral, repeated "loss" of prescriptions, tampering with
prescriptions, and reluctance to provide prior medical records or
contact information for other treating physician(s). "Doctor shopping"
to obtain additional prescriptions is common among drug abusers and
people suffering from untreated addiction;
Abuse and addiction are separate and distinct from physical dependence
and tolerance. Physicians should be aware that addiction may not be
accompanied by concurrent tolerance and symptoms of physical
dependence in all addicts. In addition, abuse of opioids can occur in
the absence of true addiction and is characterized by misuse for non-
medical purposes, often in combination with other psychoactive
substances. OxyContin, like other opioids, has been diverted for non-
medical use. Careful record keeping of prescribing information,
including quantity, frequency, and renewal requests is strongly
advised;
Proper assessment of the patient, proper prescribing practices,
periodic reevaluation of therapy, and proper dispensing and storage
are appropriate measures that help to limit abuse of opioid drugs;
OxyContin consists of a dual-polymer matrix, intended for oral use
only. Abuse of the crushed tablet poses a hazard of overdose and
death. This risk is increased with concurrent abuse of alcohol and
other substances. With parenteral abuse, the tablet excipients,
especially talc, can be expected to result in local tissue necrosis,
infection, pulmonary granulomas, and increased risk of enocarditis and
valvular heart injury. Parenteral drug abuse is commonly associated
with transmission of infectious disease such as hepatitis and HIV.".
Summary of FDA changes to original OxyContin label in 2001: Safety and
handling;
--Emphasizes the controlled status of OxyContin;
--Alerts health care professionals that OxyContin could be a target
for theft and diversion and instructs that they should contact their
State Professional Licensing Board or State Controlled Substances
Authority for information on how to prevent and detect abuse or
diversion of the product;
Language in OxyContin label approved in 2001:
"SAFETY AND HANDLING;
OxyContin Tablets are solid dosage forms that contain oxycodone which
is a controlled substance. Like morphine, oxycodone is controlled
under Schedule II of the Controlled Substances Act;
OxyContin has been targeted for theft and diversion by criminals.
Healthcare professionals should contact their State Professional
Licensing Board or State Controlled Substances Authority for
information on how to prevent and detect abuse or diversion of this
product."
Source: FDA-approved label for Purdue's OxyContin.
[End of table]
[End of section]
Appendix III: Databases Used to Monitor Abuse and Diversion of
OxyContin and Its Active Ingredient Oxycodone:
DEA uses several databases to monitor abuse and diversion of controlled
substances, including OxyContin and its active ingredient oxycodone.
Specifically, the agency monitors three major databases--the Drug Abuse
Warning Network (DAWN), the National Forensic Laboratory Information
System (NFLIS), and the System to Retrieve Information from Drug
Evidence (STRIDE).[Footnote 54] DEA also monitors other data sources to
identify trends in OxyContin abuse and diversion, such as the Substance
Abuse and Mental Health Services Administration's (SAMHSA) National
Survey on Drug Use and Health, formerly the National Household Survey
on Drug Abuse, and the Monitoring the Future Study funded by the
National Institute on Drug Abuse.[Footnote 55]
DAWN Data:
SAMHSA operates the DAWN system, which estimates national drug-related
emergency department visits and provides death counts involving abused
drugs. DAWN collects data semiannually on drug abuse from hospital
emergency department admission and medical examiner data from 21
metropolitan areas and a limited number of metropolitan medical
examiners who agree to voluntarily report medical record samples. The
emergency department and medical examiner data generally do not
differentiate oxycodone from OxyContin, unless the individual provides
the information to the hospital or identifiable tablets are found with
the person. Although samples from hospitals outside the 21 metropolitan
areas are also available, DAWN is not able to make drug-related
emergency department visit or death estimates for rural or suburban
areas.
NFLIS Data:
NFLIS, a DEA-sponsored project initiated in 1997, collects the results
of state and local forensic laboratories' analyses of drugs seized as
evidence by law enforcement agencies. NFLIS is used to track drug abuse
and trafficking involving both controlled and noncontrolled substances
and reports results by a drug's substance, such as oxycodone, and not
by its brand name. DEA stated that because new laboratories are being
added, its data should not yet be used for trending purposes. As of
March 2003, 35 state laboratories and 52 local or municipal
laboratories participated in the project.
STRIDE Data:
STRIDE, another DEA database, reports the results of chemical evidence
analysis done by DEA laboratories in drug diversion and trafficking
cases. Oxycodone data are reported by combining single and combination
oxycodone drugs and do not provide specific enough information to
distinguish OxyContin cases and exhibits. The database's lag time,
which varies by laboratory, depends on how quickly the findings are
entered after the seizure of the drug substance and its analysis.
National Survey on Drug Use and Health Data:
The National Survey on Drug Use and Health, another SAMHSA database, is
used to develop national and state estimates of trends in drug
consumption.[Footnote 56] Prior to 2001, the self-reported survey asked
participants if they had illicitly used any drug containing oxycodone.
In 2001, the survey included a separate section for pain relievers, and
asked participants if they had used OxyContin, identifying it by its
brand name, that had not been prescribed for them. State samples from
the survey are combined to make national-and state-level estimates of
drug use, and because the estimated numbers derived for OxyContin are
so small, it is not possible to project illicit OxyContin use on a
regional, state, or county basis.
Monitoring the Future Survey Data:
The Monitoring the Future Survey, funded by the National Institute on
Drug Abuse and conducted by the University of Michigan, annually
monitors the illicit use of drugs by adolescent students in the 8th,
10th, and 12th grades. The 2002 survey included new questions using the
brand names of four drugs, including OxyContin, in its survey on the
annual and 30-day prevalence of drug use.
[End of section]
Appendix IV: Comments from the Food and Drug Administration:
Food and Drug Administration
Rockville MD 20857:
November 6, 2003:
Marcia Crosse:
Director, Health Care-
Public Health and Military Health Care Issues
United States General Accounting Office
441 G Street, NW:
Washington, DC 20548:
Dear Ms. Crosse:
Please find the enclosed comments from the Food and Drug Administration
on the GAO draft report entitled, PRESCRIPTION DRUGS: Factors That May
Have Contributed to OxyContin Abuse and Diversion and Efforts to
Address the Problem, (GAO-04-110). The Agency provided technical
comments directly to your staff.
We appreciate the opportunity to review and comment on this draft
report before its publication as well as the opportunity to work with
your staff in developing this report.
Sincerely,
Mark B. McClellan, M.D., Ph.D.
Commissioner of Food and Drugs:
Signed by Mark B. McClellan
Enclosure:
General Comments by the Department of Health and Human Service's Food
and Drug Administration (FDA) on General Accounting Office's (GAO)
Draft Report. PRESCRIPTION DRUGS: Factors That May Have Contributed to
OxyContin Abuse and Diversion Efforts to Address the Problem (GAO-04-
110):
FDA appreciates the opportunity to comment on GAO's draft report which
focuses additional attention on the abuse and diversion of prescription
drugs.
We have a few general comments regarding the overall report, as
follows:
FDA's Regulation of Prescription Drugs:
As currently written, GAO's draft report suggests that FDA decided as a
matter of policy not to distinguish between types of drugs in
regulating promotion. FDA believes it is important to clarify that the
FD&C Act makes no distinction between controlled substances and other
prescription drugs in its provisions regulating promotion, but that as
a matter of general policy, the Agency more closely scrutinizes
promotion of drugs with more serious risk profiles.
OxvContin Advertisements Violated the FD&C Act:
FDA believes it is important to clarify the content of the warning
letter issued to Purdue Pharma. In January 2003, FDA issued a warning
letter to Purdue regarding two journal advertisements for OxyContin
that minimized its risks and overstated its efficacy, by failing to
present any information from the boxed warning on the potentially fatal
risks associated with OxyContin and its abuse liability, along with
omitting important information about the limitations on the indicated
use of OxyContin. The FDA requested that Purdue cease disseminating
these advertisements and any similar violative materials and provide a
plan of corrective action.
We recommend that GAO include additional information describing the
widespread dissemination of the corrective advertisement and the nature
of its content, because we believe it gives important information on
the extent to which complete and accurate information on OxyContin's
risks and its limited indication was disseminated to healthcare
providers this year resulting from the warning letter. This corrective
advertisement ran for three months and appeared in approximately 30
medical journals. The three-paged advertisement, entitled "Important
Correction of Drug Information," contained a two-paged spread, with a
"Dear Healthcare Practitioner" letter on one side, which called
attention to the warning letter and the cited violations, and directed
the reader to the boxed warning and indication information for
OxyContin prominently featured on the opposite side of the spread.
Reports of Abuse and Diversion Led to Label Changes and_ Other Actions
by FDA:
FDA recommends noting in the report that an important part of the risk
management plan in connection with the 2001 labeling changes was that
all OxyContin promotional materials be revised to reflect the labeling
changes and all future promotional materials prominently disclose this
information. As part of the risk management plan in connection with the
labeling changes, Purdue was asked to revise all of its promotional
materials for OxyContin to reflect the labeling changes. The FDA sent a
letter to Purdue, dated August 3, 2001, stating that all future
promotional materials for OxyContin should prominently disclose the
information contained in the boxed warning, the new warnings that
address misuse, abuse, diversion, and addiction, and the new
precautions and revised indication for OxyContin. Purdue agreed to
comply with this request in a letter dated August 7, 2001.
We also believe it is important to clarify that all three of the
patient videos discussed in the report were submitted prior to the
labeling change and discontinued as a result of the labeling change and
these communications. As the discussion of these patient videos is
currently written in the report, it could be misinterpreted that two of
the patient videos were submitted after the labeling change as part of
Purdue's modification of its promotional materials.
Recommendation for Executive Action:
"To improve efforts to prevent or identify the abuse and diversion of
schedule II controlled substances, the Commissioner of Food and drugs
should ensure that FDA's risk management plan guidance encourages
pharmaceutical manufacturers that submit new drug applications for
these substances to include plans that contain a strategy for
monitoring the use of these drugs and identifying potential abuse and
diversion problems.":
FDA agrees with GAO's recommendation and is currently working on the
guidance.
[End of section]
Appendix V: Comments from the Drug Enforcement Administration:
U.S. Department of Justice
Drug Enforcement Administration:
www. dea.gov:
Ms. Marcia Crosse, Director Health Care-
Public Health and Military Health Care Issues
General Accounting Office 441 G Street, N. W.
Washington, D.C. 20548:
NOV 05 2003:
Dear Ms. Crosse:
The Drug Enforcement Administration (DEA) submits the following
comments on the facts and findings of the draft report, PRESCRIPTION
DRUGS: Factors that May Have Contributed to OxyContin Abuse and
Diversion and Efforts to Address the Problem (GAO-0A-110).
In general, the report is not as forthright as warranted on the causes/
factors relating to the diversion of OxyContin. The root of the problem
that this GAO report addresses appears to be the unfortunate
convergence of Purdue's marketing techniques and the public/policy
focus on pain undertreatment. The DEA has previously stated that the
company's aggressive methods, calculated fueling of demand and the
grasp for major market share very much exacerbated OxyContin's
widespread abuse and diversion. While Purdue highlights its funding of
pain-related educational programs and websites and its partnership with
various organizations, the fact remains that Purdue's efforts-which may
be viewed as self-serving public relations damage control-would not
have been necessary had Purdue not initially marketed its product
aggressively and excessively. Contributing to the abuse and diversion
problem (and the product's excessive availability) is the fact that in
promoting this drug to practitioners, Purdue deliberately minimized the
abuse risk associated with OxyContin, as the report states on pages 21
and 35. The claim in Purdue's `educational' video for physicians that
opioid analgesics cause addiction in less than one percent of patients
is not only unsubstantiated but also dangerous because it misleads
prescribers.
In a further example of Purdue's pattern of aggressive pursuit of
market share, the report states on page 31: "As part of its marketing
campaign, Purdue distributed the usual types of branded promotional
items to health care practitioners. Among these items were OxyContin
fishing hats, stuffed plush animal toys, coffee mugs, compact discs..."
In fact, the use of such branded promotional items for a Schedule II
opioid is unprecedented. Distribution of promotional items such as
hats, plush toys and coffee mugs is an indicator of Purdue's
aggressive, excessive, and inappropriate marketing of their product,
OxyContin. The DEA suggests the Department of Health and Human Services
restrict promotional materials for Schedule II substances to items
related to the practice of medicine or pharmacy.
Increased availability of controlled substances leads to increased
opportunities for diversion. Therefore, it is essential that stringent
risk management plans are put in place prior to the introduction of
these products into the marketplace.
Unfortunately, there are limitations to DEA's ability to document the
extent of diversion of specific products and DEA agrees with GAO's
observation, on the bottom of page 36 of the draft report, that "data
on abuse and diversion are not reliable, comprehensive, or timely." DEA
also advocates the development of a system to provide "credible,
legally defensible evidence concerning drug abuse trends in America,"
as stated on page 42 of the draft report. DEA included an additional
$750,000 in its 2003 budget request for an enhanced scientific data
collection system that would include a National Medical Examiner
Information System; however, this request has not been funded. This
agency welcomes a recommendation by GAO that more reliable,
comprehensive and timely databases be developed.
In addition, there are minor inaccuracies in this report, detailed
below:
First remark, ref page 3, 2nd full sentence of GAO draft report: DEA
suggests the following edit to the draft report language (new/
replacement language is in bold italics): "Unlike nonopioid pain
relievers, oxycodone, the active ingredient in OxyContin, has no known
analgesic hits no ceiling effect, that is, the dose amount a patient
can take can be increased by the physician as needed to relieve pain.
However, as the dose escalates, there is always a danger ofserious side
effects, including respiratory depression and death.":
* Page 5, line 9: refers to "...three other opioid drugs, Avinza,
Kadian, and Oramorph SR, that like OxyContin are classified as schedule
II controlled substances." These drugs should be further identified as
high dose extended release opioid drugs, not simply "opioid drugs,"
here and throughout this document.
* Page 18, first paragraph: states "...a prescription for a schedule II
drug may not be refilled, and the patient must see the practitioner
again in order to obtain more drugs." While it is correct that schedule
II drug prescriptions may not be refilled, a patient is not required to
see the practitioner again but must obtain a new prescription.
Please correct the document language noted above to ensure the report's
accuracy. The DEA appreciates the opportunity to provide comment to the
GAO in these important matters.
Sincerely,
Rogelio Guevara:
Chief Inspector:
Signed by Rogelio Guevara:
[End of section]
FOOTNOTES
[1] OxyContin is an opioid analgesic--a narcotic substance that
relieves a person's pain without causing the loss of consciousness.
Hereafter, we refer to the company as Purdue.
[2] As discussed later in this report, FDA approved the revised
OxyContin label in July 2001 to describe the time frame as "when a
continuous around-the-clock analgesic is needed for an extended period
of time."
[3] According to FDA, there is no known limit to the amount of
oxycodone, the active ingredient in OxyContin, that can be used to
treat pain.
[4] Prescription drug diversion can involve such activities as "doctor
shopping" by individuals who visit numerous physicians to obtain
multiple prescriptions, prescription forgery, and pharmacy theft.
Diversion can also involve illegal sales of prescription drugs by
physicians, patients, or pharmacists, as well as obtaining controlled
substances from Internet pharmacies without a valid prescription.
[5] According to the National Institute on Drug Abuse, addiction is a
chronic, relapsing disease, characterized by compulsive drug seeking
and use and by neurochemical and molecular changes in the brain,
whereas physical dependence is an adaptive physiological state that can
occur with regular drug use and results in withdrawal symptoms when
drug use is discontinued.
[6] Under the Controlled Substances Act, which was enacted in 1970,
drugs are classified as controlled substances and placed into one of
five schedules based on their medicinal value, potential for abuse, and
safety or dependence liability. Schedule I drugs have no medicinal
value; have not been approved by FDA; and along with schedule II drugs,
have the highest potential for abuse. Schedule II drugs have the
highest potential for abuse of any approved drugs.
[7] OxyContin, Hearings of the Subcommittee on the Departments of
Commerce, Justice, and State, the Judiciary, and Related Agencies,
House Committee on Appropriations, 107th Cong. Part 10 (Dec. 11, 2001).
[8] OxyContin: Balancing Risks and Benefits, Hearing of the Senate
Committee on Health, Education, Labor, and Pensions, 107th Cong. 287
(Feb. 12, 2002).
[9] Avinza was approved by FDA in 2002 and is marketed by Ligand
Pharmaceuticals; Kadian was approved in 1996 and is marketed by
Alpharma-US Human Pharmaceuticals; and Oramorph SR was approved in 1991
and is now owned by —lan Corporation, which told us it is not currently
marketing the drug.
[10] Title II of the Comprehensive Drug Abuse Prevention and Control
Act of 1970 (Pub. L. No. 91-513, §§100 et seq., 84 Stat. 1236, 1242 et
seq.).
[11] The other four vital signs physicians use to assess patients are
pulse, blood pressure, core temperature, and respiration.
[12] In 1999, the name of the Agency for Health Care Policy and
Research was changed to the Agency for Healthcare Research and Quality.
The agency, which is part of HHS, is responsible for supporting
research designed to improve the quality of health care, reduce its
costs, and broaden access to essential services.
[13] When we refer to OxyContin's label we are also referring to the
drug's package insert that contains the same information about the
product.
[14] For example, according to Purdue's comparable dose guide a patient
taking one Percodan 4.5-milligram tablet or one Tylox 5-milligram
tablet every 6 hours can be converted to either a 10-or a 20-milligram
OxyContin tablet to be taken every 12 hours. For a 12-hour dosing
period, one OxyContin tablet replaces two Percodan or Tylox tablets,
and one OxyContin tablet contains twice as much oxycodone as one of the
other tablets.
[15] In April 2001, Purdue discontinued distribution of the 160-
milligram tablets because of OxyContin abuse and diversion concerns.
[16] Doris Bloodsworth, "Pain Pill Leaves Death Trail: A Nine-Month
Investigation Raises Many Questions about Purdue Pharma's Powerful Drug
OxyContin," Orlando Sentinel, Oct. 19, 2003.
[17] Section 201, classified to 21 U.S.C. § 811.
[18] Some schedule V drugs that contain limited quantities of certain
narcotic and stimulant drugs are available over the counter, without a
prescription.
[19] FDA regulations require that promotional labeling and
advertisements be submitted to FDA at the time of initial dissemination
(for labeling) and initial publication (for advertisements). The FD&C
Act defines labeling to include all labels and other written, printed,
or graphic matter accompanying an article. For example, promotional
materials commonly shown or given to physicians, such as sales aids and
branded promotional items, are regulated as promotional labeling. FDA
may also regulate promotion by sales representatives on computer
programs, through fax machines, or on electronic bulletin boards.
[20] For details on FDA's oversight of drug advertising see U.S.
General Accounting Office, Prescription Drugs: FDA Oversight of Direct-
to-Consumer Advertising Has Limitations, GAO-03-177 (Washington, D.C.:
Oct. 28, 2002).
[21] The Prescription Drug User Fee Act of 1992, Pub. L. No. 102-571,
title I, 106 Stat. 4491, was reauthorized by the Food and Drug
Modernization Act of 1997, Pub. L. No. 105-115, 111 Stat. 2296, and,
most recently, by the Prescription Drug User Fee Amendments of 2002,
Pub. L. No. 107-188, title V, subtitle A, 116 Stat. 594, 687.
[22] For more details on Internet pharmacies, see U.S. General
Accounting Office, Internet Pharmacies: Adding Disclosure Requirements
Would Aid State and Federal Oversight, GAO-01-69 (Washington, D.C.:
Oct. 19, 2000).
[23] For more details on these programs, see U.S. General Accounting
Office, Prescription Drugs: State Monitoring Programs Provide Useful
Tool to Reduce Diversion, GAO-02-634 (Washington, D.C.: May 17, 2002).
[24] In addition, the American Medical Association, a professional
association for physicians, issued guidelines in 1990 regarding gifts
given to physicians by drug industry representatives. For example,
physicians may accept individual gifts of nominal value that are
related to their work, such as notepads and pens, and may attend
conferences sponsored by drug companies that are educational and for
which appropriate disclosure of financial support or conflicts of
interest is made.
[25] Following OxyContin's July 2001 label change, Purdue modified its
promotional messages but continued to focus on encouraging physicians
to prescribe OxyContin for patients taking pain relievers every 4 to 6
hours. In 2003, Purdue began using the promotional claim "there can be
life with relief" in OxyContin promotion.
[26] IMS Health reported noncancer prescriptions written for the
following types of pain conditions: surgical aftercare; musculoskeletal
disorders including back and neck disorders, arthritis conditions, and
injuries and trauma including bone fractures; central nervous system
disorders including headache conditions such as migraines;
genitourinary disorders including kidney stones; and other types of
general pain.
[27] The IMS Health data included information from the National Disease
and Therapeutics Index and the National Prescription Audit. The
National Disease and Therapeutics Index does not capture data from
anesthesiologists and dental specialties. The National Prescription
Audit data include retail pharmacy, long-term-care, and mail-order
prescriptions.
[28] Duragesic is a skin patch used to deliver the opioid pain reliever
fentanyl over a 72-hour period.
[29] These sales representatives were also responsible for promoting
other Purdue products.
[30] Abbott Laboratories sales representatives' promotion of OxyContin
is limited to hospital-based anesthesiologists and surgeons and major
hospitals, medical centers, and freestanding pain clinics.
[31] U.S. General Accounting Office, Prescription Drugs: FDA Oversight
of Direct-to-Consumer Advertising Has Limitations, GAO-03-177
(Washington, D.C.: Oct. 28, 2002).
[32] During 2000 through 2002, JCAHO sponsored a series of educational
programs on pain management standards with various cosponsors,
including pain-related groups such as the American Pain Society and the
American Academy of Pain Medicine.
[33] The "Find a Doctor" feature is a physician listing service
provided by the National Physicians DataSource, LLC.
[34] Purdue has also helped to fund the Dannemiller Memorial Education
Foundation and the American Academy of Physician Assistants Web sites.
[35] It is common drug industry practice for companies to provide
conversion tables for sales representatives to distribute to health
care practitioners. Purdue used a similar pen for its older product, MS
Contin.
[36] FDA indicated that in 2000, it issued 75 untitled letters to 46
drug manufacturers, as well as 4 warning letters to 4 drug
manufacturers, for using promotional activities that violated the FD&C
Act.
[37] The advertisement appeared in the New England Journal of Medicine
in May 2000.
[38] The advertisements appeared in the Journal of the American Medical
Association in October and November 2002.
[39] According to FDA, the corrective advertisement ran for 3 months
and appeared in approximately 30 medical journals.
[40] FDA indicated that from January through August 2003, it issued 4
warning letters to four manufacturers and 12 untitled letters to seven
drug manufacturers for using promotional activities that violated the
FD&C Act.
[41] Zeneca Pharmaceuticals promoted Kadian for Faulding Laboratories,
the drug's manufacturer at that time.
[42] See, for example, G.B. Curtis, et al. "Relative Potency of
Controlled-Release Oxycodone and Morphine in a Postoperative Pain
Model," European Journal of Clinical Pharmacology, vol. 55, no. 6
(1999): 55:425-429.
[43] This information is from the National Institute for Health Care
Management's Prescription Drug Expenditures reports for 2000 and 2001,
prepared using American Institutes for Research analysis of Scott-Levin
Prescription Audit Data. OxyContin was ranked 18th in 2000.
[44] In making a designation, ONDCP considers whether the geographic
area is a center of drug production, manufacturing, importation, or
distribution; whether state and local law enforcement agencies have
committed resources to respond aggressively to the drug trafficking
problem; whether drug activities in the area are having a harmful
impact on other areas of the country; and whether a significant
increase in federal resources is necessary to respond to the area's
drug-related activities.
[45] Appalachia High Intensity Drug Trafficking Area Task Force, The
OxyContin Threat in Appalachia (London, Ky.: August 2001).
[46] The reliability of the data collected depends on whether the
emergency room patient visit was reported as drug related, whether the
patient reported taking a particular drug, and whether the emergency
room physician indicated a drug's brand name in the patient's medical
record.
[47] See app. III for more details on the abuse and diversion databases
DEA uses.
[48] The 15 states are Alabama, Arizona, Colorado, Connecticut,
Florida, Louisiana, Massachusetts, Mississippi, Missouri, New Jersey,
North Carolina, South Carolina, Texas, Washington, and Wisconsin.
[49] Hydrocodone products, such as Anexsia, Hycodan, Lorcet, Lortab,
and Vicodin, remain among the most abused and diverted scheduled
prescription drugs nationally.
[50] See www.fda.gov/cder/drug/infopage/oxycontin/default.htm.
[51] The Kentucky guidelines for the use of controlled substances in
pain treatment provide that (1) a complete medical history and
examination be conducted and documented in patient medical records, (2)
a written treatment plan state objectives for determining treatment
success, (3) the risks and benefits of the use of controlled substances
be discussed by physician and patient, (4) periodic review of the
course of treatment be conducted, (5) consultation or referral to an
expert in pain management be considered for patients who are at risk
for substance abuse, (6) patient's medical record be kept accurate and
complete, and (7) physicians be in compliance with applicable federal
and state controlled substance laws and regulations.
[52] Amended versions of Purdue's risk management plan for OxyContin
were submitted to FDA for review in April 2002 and in March 2003.
[53] RADARS will collect information on brand-name and generic versions
of buprenorphine, fentanyl, hydrocodone, hydromorphone, oxycodone,
morphine, and methadone. Benzodiazepine is scheduled to be added to
RADARS in late 2003.
[54] Other databases used by DEA to assess changes in drug abuse and
diversion include the Drug Early Warning System, the Drug and Alcohol
Services Information System, the Treatment Episode Data Set, the
National Survey of Substance Abuse Treatment Services, the Uniform
Facility Data Set, the Poison Control Center Data or Toxic Exposure
Surveillance System, the Automation of Reports and Consolidated
Ordering System, the DEA Theft System, and the DEA Field Reports and
Investigative Teletypes.
[55] The National Institute on Drug Abuse is part of the National
Institutes of Health within the Department of Health and Human
Services.
[56] Self-reporting individuals are interviewed regarding their illicit
drug use over three periods--within the last 30 days, during the past
year, and during their lifetime. The survey data are limited, as it is
not possible to determine specifically which year respondents may have
used a drug illicitly, because they are asked both whether they have
ever used the drug illicitly in their lifetime and whether they have
used it during the past year.
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